Venous thrombo-embolism as a complication of cross-sex hormone treatment of male-to-female transsexual subjects: a review

Administration of cross-sex hormones to male-to-female transsexual subjects, usually oestrogens + often anti-androgens, such as cyproterone acetate, carries a risk of venous thromboembolism (VTE). VTE usually occurs in the first year of oestrogen administration. Ethinyl oestradiol, due to its chemical structure, was in 2003 identified as a major factor in the occurrence of VTE. Most clinics do not prescribe ethinyl oestradiol any longer, but people who take hormones without medical supervision use often oral contraceptives containing ethinyl oestradiol, many times in overdose. Cessation of use of ethinyl oestradiol and peri-operative thrombosis prophylaxis for surgery have reduced prevalence rate of VTE. Other oral oestrogens should not be overdosed, and transdermal oestrogen is to be preferred. Thrombosis prophylaxis for surgery is mandatory. It seems advisable to stop hormone use at least 2 weeks before major surgery, to be resumed only after 3 weeks following full mobilisation.

Regulation of androgen biosynthesis - A short review and preliminary results from the hyperandrogenic starvation NCI-H295R cell model

Regulation of androgen production is poorly understood. Adrenarche is the physiologic event in mid-childhood when the adrenal zona reticularis starts to produce androgens through specific expression of genes for enzymes and cofactors necessary for androgen synthesis. Similarly, expression and activities of same genes and products are deregulated in hyperandrogenic disorders such as the polycystic ovary syndrome (PCOS). Numerous studies revealed involvement of several signaling pathways stimulated through G-protein coupled receptors or growth factors transmitting their effects through cAMP- or non-cAMP-dependent signaling. Overall a complex network regulates androgen synthesis targeting involved genes and proteins at the transcriptional and post-translational levels. Newest players in the field are the DENND1A gene identified in PCOS patients and the MAPK14 which is the kinase phosphorylating CYP17 for enhanced lyase activity. Next generation sequencing studies of PCOS patients and transcriptome analysis of androgen producing tissues or cell models provide newer tools to identify modulators of androgen synthesis.

Steroidogenesis of the testis - new genes and pathways

Defects of androgen biosynthesis cause 46,XY disorder of sexual development (DSD). All steroids are produced from cholesterol and the early steps of steroidogenesis are common to mineralocorticoid, glucocorticoid and sex steroid production. Genetic mutations in enzymes and proteins supporting the early biosynthesis pathways cause adrenal insufficiency (AI), DSD and gonadal insufficiency. The classic androgen biosynthesis defects with AI are lipoid CAH, CYP11A1 and HSD3B2 deficiencies. Deficiency of CYP17A1 rarely causes AI, and HSD17B3 or SRD5A2 deficiencies only cause 46,XY DSD and gonadal insufficiency. All androgen biosynthesis depends on 17,20 lyase activity of CYP17A1 which is supported by P450 oxidoreductase (POR) and cytochrome b5 (CYB5). Therefore 46,XY DSD with apparent 17,20 lyase deficiency may be due to mutations in CYP17A1, POR or CYB5. Illustrated by patients harboring mutations in SRD5A2, normal development of the male external genitalia depends largely on dihydrotestosterone (DHT) which is converted from circulating testicular testosterone (T) through SRD5A2 in the genital skin. In the classic androgen biosynthetic pathway, T is produced from DHEA and androstenedione/-diol in the testis. However, recently found mutations in AKR1C2/4 genes in undervirilized 46,XY individuals have established a role for a novel, alternative, backdoor pathway for fetal testicular DHT synthesis. In this pathway, which has been first elucidated for the tammar wallaby pouch young, 17-hydroxyprogesterone is converted directly to DHT by 5α-3α reductive steps without going through the androgens of the classic pathway. Enzymes AKR1C2/4 catalyse the critical 3αHSD reductive reaction which feeds 17OH-DHP into the backdoor pathway. In conclusion, androgen production in the fetal testis seems to utilize two pathways but their exact interplay remains to be elucidated.

Ovarian and uterine development and hormonal feedback mechanism in a 46 XX patient with CYP19A1 deficiency under low dose estrogen replacement.

Abstract Background: Aromatase deficiency may result in a complete block of estrogen synthesis because of the failure to convert androgens to estrogens. In females, this results in virilisation at birth, ovarian cysts in prepuberty and lack of pubertal development but virilisation, thereafter. Objective and methods: We studied the impact of oral 17β-estradiol treatment on ovarian and uterine development, and on LH/FSH and inhibin B during the long-term follow-up of a girl harboring compound heterozygote point mutations in the CYP19A1 gene. Results: In early childhood, low doses of oral 17β-estradiol were needed. During prepuberty treatment with slowly increasing doses of E2 resulted in normal uterine and almost normal development of ovarian volume, as well as number and size of follicles. Regarding hormonal feedback mechanisms, inhibin B levels were in the upper normal range during childhood and puberty. Low doses of estradiol did not suffice to achieve physiological gonadotropin levels in late prepuberty and puberty. However, when estradiol doses were further increased in late puberty levels of both FSH and LH declined with estradiol levels within normal range. Conclusion: Complete aromatase deficiency provides an excellent model of how ovarian and uterine development in relation to E2, LH, FSH and inhibin B feedback progresses from infancy to adolescence.

[Klinik und Diagnose von Hypogonadismus und Andropause]

Diagnosis and therapy of male hypogonadism is still a challenge because of the unspecific clinical signs and symptoms. The clinical presentation of a androgen deficiency is age-related. In the adult men, one can often observe fatigue, decrease in physical capacity, loss of libido and erectile dysfunction. At the physical examination, genitalia have always to be assessed in search of a testes/penis atrophy. Two fasting measurements of total testosterone concentrations by a reliable assay are needed to confirm the diagnosis. By assessing gonadotropines the origin of hypogonadism can be determined (central/secondary or peripheral/primary). Exogenous administration of androgens should be considered in young, sportive, healthy and muscular males. Patients with metabolic syndrome should only be screened for hypogonadism in the presence of suggestive symptoms. Prostate disease, hematocrit higher than 50 %, uncontrolled heart failure and severe obstructive sleep apnea are contraindications of a testosterone replacement therapy. Patients with metabolic-syndrome-associated low testosterone levels should firstly benefit from a lifestyle intervention that can normalize clinical and biochemical hypogonadism. So far, there is no clear evidence for a possible benefit of testosterone therapy in patients with the metabolic syndrome. Similarly, in patients with PADAM (partial androgen deficiency of the aging male) testosterone therapy is not established or recommended.

Estimation of reference curves for the urinary steroid metabolome in the first year of life in healthy children: tracing the complexity of human postnatal steroidogenesis

CONTEXT Complex steroid disorders such as P450 oxidoreductase deficiency or apparent cortisone reductase deficiency may be recognized by steroid profiling using chromatographic mass spectrometric methods. These methods are highly specific and sensitive, and provide a complete spectrum of steroid metabolites in a single measurement of one sample which makes them superior to immunoassays. The steroid metabolome during the fetal-neonatal transition is characterized by a) the metabolites of the fetal-placental unit at birth, b) the fetal adrenal androgens until its involution 3-6 months postnatally, and c) the steroid metabolites produced by the developing endocrine organs. All these developmental events change the steroid metabolome in an age- and sex-dependent manner during the first year of life. OBJECTIVE The aim of this study was to provide normative values for the urinary steroid metabolome of healthy newborns at short time intervals in the first year of life. METHODS We conducted a prospective, longitudinal study to measure 67 urinary steroid metabolites in 21 male and 22 female term healthy newborn infants at 13 time-points from week 1 to week 49 of life. Urine samples were collected from newborn infants before discharge from hospital and from healthy infants at home. Steroid metabolites were measured by gas chromatography-mass spectrometry (GC-MS) and steroid concentrations corrected for urinary creatinine excretion were calculated. RESULTS 61 steroids showed age and 15 steroids sex specificity. Highest urinary steroid concentrations were found in both sexes for progesterone derivatives, in particular 20α-DH-5α-DH-progesterone, and for highly polar 6α-hydroxylated glucocorticoids. The steroids peaked at week 3 and decreased by ∼80% at week 25 in both sexes. The decline of progestins, androgens and estrogens was more pronounced than of glucocorticoids whereas the excretion of corticosterone and its metabolites and of mineralocorticoids remained constant during the first year of life. CONCLUSION The urinary steroid profile changes dramatically during the first year of life and correlates with the physiologic developmental changes during the fetal-neonatal transition. Thus detailed normative data during this time period permit the use of steroid profiling as a powerful diagnostic tool.

Retinoic acid receptor beta and angiopoietin-like protein 1 are involved in the regulation of human androgen biosynthesis

Androgens are essential for sexual development and reproduction. However, androgen regulation in health and disease is poorly understood. We showed that human adrenocortical H295R cells grown under starvation conditions acquire a hyperandrogenic steroid profile with changes in steroid metabolizing enzymes HSD3B2 and CYP17A1 essential for androgen production. Here we studied the regulatory mechanisms underlying androgen production in starved H295R cells. Microarray expression profiling of normal versus starved H295R cells revealed fourteen differentially expressed genes; HSD3B2, HSD3B1, CYP21A2, RARB, ASS1, CFI, ASCL1 and ENC1 play a role in steroid and energy metabolism and ANGPTL1, PLK2, DUSP6, DUSP10 and FREM2 are involved in signal transduction. We discovered two new gene networks around RARB and ANGPTL1, and show how they regulate androgen biosynthesis. Transcription factor RARB stimulated the promoters of genes involved in androgen production (StAR, CYP17A1 and HSD3B2) and enhanced androstenedione production. For HSD3B2 regulation RARB worked in cooperation with Nur77. Secretory protein ANGPTL1 modulated CYP17A1 and DUSP6 expression by inducing ERK1/2 phosphorylation. By contrast, our studies revealed no evidence for hormones or cell cycle involvement in regulating androgen biosynthesis. In summary, these studies establish a firm role for RARB and ANGPTL1 in the regulation of androgen production in H295R cells.

Regulation of human (adrenal) androgen biosynthesis-New insights from novel throughput technology studies

Androgens are precursors for sex steroids and are predominantly produced in the human gonads and the adrenal cortex. They are important for intrauterine and postnatal sexual development and human reproduction. Although human androgen biosynthesis has been extensively studied in the past, exact mechanisms underlying the regulation of androgen production in health and disease remain vague. Here, the knowledge on human androgen biosynthesis and regulation is reviewed with a special focus on human adrenal androgen production and the hyperandrogenic disorder of polycystic ovary syndrome (PCOS). Since human androgen regulation is highly specific without a good animal model, most studies are performed on patients harboring inborn errors of androgen biosynthesis, on human biomaterials and human (tumor) cell models. In the past, most studies used a candidate gene approach while newer studies use high throughput technologies to identify novel regulators of androgen biosynthesis. Using genome wide association studies on cohorts of patients, novel PCOS candidate genes have been recently described. Variant 2 of the DENND1A gene was found overexpressed in PCOS theca cells and confirmed to enhance androgen production. Transcriptome profiling of dissected adrenal zones established a role for BMP4 in androgen synthesis. Similarly, transcriptome analysis of human adrenal NCI-H295 cells identified novel regulators of androgen production. Kinase p38α (MAPK14) was found to phosphorylate CYP17 for enhanced 17,20 lyase activity and RARB and ANGPTL1 were detected in novel networks regulating androgens. The discovery of novel players for androgen biosynthesis is of clinical significance as it provides targets for diagnostic and therapeutic use.