Ariel Rösler

Treatment of men with paraphilia with a long-acting analogue of gonadotropin-releasing hormone

BACKGROUND Men with deviant sexual behavior, or paraphilia, are usually treated with psychotherapy, antidepressant drugs, progestins, and antiandrogens, but these treatments are often ineffective. Selective inhibition of pituitary-gonadal function with a long-acting agonist analogue of gonadotropin-releasing hormone may abolish the deviant sexual behavior by reducing testosterone secretion. METHODS In an uncontrolled observational study, we treated 30 men (mean age, 32 years) with severe long-standing paraphilia (25 with pedophilia and 5 with other types of abnormal behavior) with monthly injections of 3.75 mg of triptorelin and supportive psychotherapy for 8 to 42 months. The efficacy of therapy was evaluated monthly by the Intensity of Sexual Desire and Symptoms Scale and yearly by the Three Main Complaints questionnaire. RESULTS All the men had a decrease in the number of deviant sexual fantasies and desires, from a mean (+/-SD) of 48+/-10 per week before therapy to zero during therapy (P<0.001), and a decrease in the number of incidents of abnormal sexual behavior (from 5+/-2 per month to zero, P<0.001) while receiving triptorelin. These effects were evident after 3 to 10 months of therapy (P<0.001) and persisted in all 24 men who continued therapy for at least 1 year. The mens mean serum testosterone concentration fell from 545+/-196 ng per deciliter (18.9+/-6.8 nmol per liter) before therapy to 23+/-14 ng per deciliter (0.8+/-0.5 nmol per liter, P<0.001) after 42 months of triptorelin. The main side effects were erectile failure, hot flashes, and decrease in bone mineral density in some men. CONCLUSIONS Continuous administration of triptorelin, a long-acting agonist analogue of gonadotropin-releasing hormone, together with supportive psychotherapy, may be an effective treatment for men with severe paraphilia.

Direct correlation between plasma renin activity and severity of the ovarian hyperstimulation syndrome

Plasma renin activity (PRA) and aldosterone were measured throughout the luteal phase in 21 anovulatory patients who developed ovarian hyperstimulation syndrome (OHSS) during menotropin induction of ovulation. The pattern of PRA in hyperstimulated cycles is characterized by a midluteal peak, which declines to normal in the late luteal phase in nonconceptual cycles, whereas a sustained elevation of PRA occurs in conceptual cycles. Midluteal PRA is significantly (P less than 0.001) elevated in patients with OHSS compared with controls. In the mild form of the disease, the median of PRA is 7.5 (range 6 to 11) ng angiotensin I (AI)/ml/hr, significantly higher than the median for controls, 3.0 ng AI/ml/hr (range, 1.4 to 5). In moderate OHSS, PRA was 24.5 (range, 10 to 40) ng AI/ml/hr, whereas, in the severe form of OHSS, PRA was 55.0 (range, 29 to 95) ng AI/ml/hr. A significant correlation (P less than 0.05) was demonstrated between PRA and either progesterone or 17 beta estradiol (E2). The renin-angiotensin cascade is implicated in new vessel formation. Angiogenesis itself is associated with a rapid increase in capillary permeability. The recent demonstration of high plasma renin-like activity in human follicular fluid and the present observation of high PRA in patients with OHSS may imply that the locally active renin angiotensin system, through induction of new vessel formation and increase in capillary permeability, may have a casual relationship to the ovarian enlargement and extracellular fluid accumulation that are the hallmarks of OHSS.

Clinical Variability of Congenital Adrenal Hyperplasia due to 11β-Hydroxylase Deficiency

Studies in 18 Jewish families from Morocco, Tunis, Turkey and Iran revealed 26 patients with congenital adrenal hyperplasia due to 11β-hydroxylase deficiency. The clinical expression of androgen exces

Steroid 17β-hydroxysteroid dehydrogenase deficiency in man: an inherited form of male pseudohermaphroditism.

Sixty-eight males with testicular 17β-hydroxysteroid dehydrogenase deficiency (17β-HSD) were identified among a highly inbred Arab population in Israel, and 45 studied over the last 15 years. The founders of this defect originated in the mountainous region of present Lebanon and Syria, but most of the families now live in Jerusalem, Hebron, the Tel-Aviv area, and in particular Gaza, where the frequency of affected males is estimated at 1 in 100 to 150. Affected individuals (46,XY) are born with ambiguity of the genitalia and reared as females until puberty. Thereafter marked virilization occurs, leading in many cases to the spontaneous adoption of a male gender role. Adults develop a male habitus with abundant body hair and beard, and the phallus and testes enlarge to adult proportions. Gender reassignment was possible only when enough erectile tissue was present at birth and developed into a normal size penis with systemic testosterone. male genitoplasty was performed in 15 children and 8 post-pubertal patients, and female genitoplasty in 2 children and 4 post-pubertal patients. In adults the defect is characterized by markedly increased concentrations of 4-androstendione (4-A) with borderline low to normal testosterone (T) levels, and a high 4-A/T ratio. Dihydrotestosterone (DHT) concentrations were either moderately decreased, normal, or high, and dehydroepiandrosterone levels were high. The estrogen pathway was also impaired, even though both estrone and estradiol-17β levels were elevated. Children had low basal levels of all androgens, but the defect could be demonstrated after prolonged stimulation with human chorionic gonadotropin. LH and FSH levels were very high after puberty, and normal in childhood. However, an over-response to gonadotropin-releasing hormone was found at all ages. Studies in testicular tissue revealed various abnormalities in steroid metabolism. Tissue from pre-pubertal patients metabolized progesterone (P) only to 4-A, while tissue from post-pubertal patients metabolized P to 16α- and 16β-hydroxyprogesterone (5.4- to 10.3-fold greater production), 17α-hydroxyprogesterone (5.4- to 8-fold smaller production), 4-A and T. 4-A was also metabolized to T, indicating that 17β-HSD was no longer deficient. Flow studies with equimolar concentrations of [¹⁴C]P and [³H]pregnenolone showed that the 5-ene pathway was the preferential one for androgen biosynthesis. Both in vivo and in vitro studies indicate that the severity of testicular 17β-HSD deficiency changes with age. Whereas the enzyme activity is absent in childhood, there is a progressive restoration after puberty. Androgen production increases progressively to normal so that T and DHT concentrations are sufficiently high to gradually induce somatic and genital virilization, thus enabling an adequate male gender function.

11‐DEOXYCORTISOL IN AMNIOTIC FLUID: PRENATAL DIAGNOSIS OF CONGENITAL ADRENAL HYPERPLASIA DUE TO 11 β‐HYDROXYLASE DEFICIENCY

The mean control level of 11‐deoxycortisol as determined by radioimmunoassay in eighty‐one human amniotic fluid samples was 1·20 ± 0·07 ng/ml. Markedly elevated levels were found at term in amniotic fluid of two pregnancies with fetuses affected with 11 β‐hydroxylase deficiency, congenital adrenal hyperplasia (135·0 and 64·0 ng/ml respectively) as well as in the maternal serum of one of these cases (28·0 ng/ml). It is suggested that the determination of 11‐deoxycortisol in amniotic fluid be a prenatal diagnostic test for 11 β‐hydroxylase deficiency congenital adrenal hyperplasia.

Mutations in human 11β-hydroxylase genes: 11β-hydroxylase deficiency in Jews of Morocco and corticosterone methyl-oxidase II deficiency in Jews of Iran

Abstract Steroid 11β-hydroxylase is encoded by two homologous genes, CYP11B1 and CYP11B2, located on chromosome 8q21–22. CYP11B1 encodes a specific cytochrome P -450 ( P -450c11) necessary for cortisol biosynthesis, with predominantly 11β-hydroxylase and moderate 18-hydroxylase activity, whereas CYP11B2 encodes another isozyme ( P -450cmo) necessary for aldosterone biosynthesis, with 11β-hydroxylase, 18-hydroxylase and 18-oxidase activities (the latter two termed corticosterone methyl-oxidase I and II; CMO-I and II, respectively). Two steroid biosynthetic defects, both relatively frequent in Israel, are caused by specific mutations in each of these genes. 11β-Hydroxylase deficiency is frequent among Jews from Morocco (1 in 5000 to 7000 births), and is characterized by virilization, hypertension, impaired cortisol biosynthesis, and increased deoxycorticosterone and androgens. Affected individuals have a single base substitution in exon 8 of CYP11B1, codon 448, from CGC (arginine) to CAC (histidine). This sequence, normally absent in CYP11B2, constitutes a true point mutation within the heme binding domain of CYP11B1 that results in marked impairment of enzymatic activity. The clinical expression is characterized by a wide range of variability in the signs of both androgen and mineralocorticoid excess, even though an identical mutation was found in all but one of the affected alleles examined. CMO-II deficiency is frequent among Jews from Iran (1 in 4000 births), and is characterized by a typical salt-wasting syndrome, increased 18-hydroxycorticosterone, impaired aldosterone biosynthesis, and a high ratio of these steroids. No mutation was found in CYP11B1, but all individuals affected were homozygous for two missense mutations in CYP11B2. The first, in exon 3, codon 181, from CGC (arginine) to TGG (tryptophane) is a mutation that completely abolishes both CMO-I and II activities, whereas the second, in exon 7, codon 386, from GTG (valine) to GCG (alanine) is a more conservative substitution that produces only a minimal reduction in CMO-I activity. Individuals homozygous for either one of these mutations are asymptomatic.

Selective hypoaldosteronism in Iranian Jews: An autosomal recessive trait

A salt‐wasting syndrome associated with high plasma renin activity and inappropriately low aldosterone levels was observed among eight Jewish families from Iran. Aldosterone deficiency was due to an inborn error selectively involving the terminal portion of the biosynthetic pathway and characterized by an enzymic block in the conversion of 18‐hydroxycorticosterone to aldosterone. The analysis of the eight pedigrees, including 12 affected children, shows a high coefficient of inbreeding. Genetic analysis, by two independent methods, strongly suggests an autosomal recessive mode of transmission of the syndrome.

Subclinical hypothyroidism in infertile women: the importance of continuous monitoring and the role of the thyrotropin-releasing hormone stimulation test.

The aim of our study was to assess the prevalence of subclinical hypothyroidism (SH) after administering a thyrotropin-releasing hormone (TRH) stimulation test among women with normal serum thyroid-stimulating hormone (TSH) levels and various causes of infertility. Eighty-seven infertile women (39 with ovulation disorders and 48 with other causes of infertility) had a TRH stimulation test on day 3 – 7 of their cycle. Exaggerated TSH response (>30 mIU/l at 20, 40 or 60 min) following intravenous injection of 400 µg TRH was defined as SH. The TRH test was performed 2 – 4 months after the first visit to the clinic. We found that the prevalence of SH was significantly higher among women with ovulation disorders (20.5%) than among women with normal ovulation (8.3%). In addition, we found that although basal TSH levels were normal at recruitment, 2 – 4 months later these levels were abnormally high in 8% of the women. All these women had an abnormal TRH test. We recommend performing TRH stimulation testing in women suffering from ovulation disorders who have normal basal TSH levels, followed by repeat assessments of thyroid function to enable treatment with thyroxine in cases with abnormal results.

Chromatin-positive Klinefelter's syndrome with undetectable peripheral FSH levels

An 18 year old phenotypic man is described with chromatin-positive Klinefelters syndrome and undetectable peripheral human follicle stimulating hormone levels. The subject manifested chromosomal mosaicism consisting of three stem cell lines (45X; 46XY; and 47XXY). Testicular biopsy specimen showed germinal cell aplasia: the tubules were lined by Sertoli cells only, whereas the Leydig cells appeared normal. Serum human follicle stimulating hormone levels were undetectable and rose to only 5 mIU/ml after the administration of luteinizing hormone releasing hormone. Serum human luteinizing hormone varied between normal and moderately elevated values, and serum testosterone was in the low normal range. We discuss the features which distinguish this syndrome from isolated gonadotropin deficiency and from classic germinal cell aplasia. We suggest that the patient represents a new variant of Klinefelters syndrome, with failure of human follicle stimulating hormone release secondary to prolonged hypersecretion.

Pseudohypoaldosteronism due to renal and multisystem resistance to mineralocorticoids respond differently to carbenoxolone.

Type I pseudohypoaldosteronism (PHA) is a hereditary syndrome of salt wasting resulting from unresponsiveness to mineralocorticoids. PHA is manifested in two clinically and genetically distinct forms, affecting either only the kidney or multiple target organs of aldosterone. We examined the mineralocorticoid effect of carbenoxolone (CBX) in young PHA patients with either renal or multisystem resistance to aldosterone to find out whether CBX may help reduce the requirement for a high-salt diet. CBX did not show any significant salt-retaining effect in two patients with multiple PHA, and did not affect the renin-aldosterone system. In contrast, CBX significantly suppressed the renin-aldosterone system in a renal PHA patient for the whole duration of treatment, but without a long-term salt-retaining effect. On CBX treatment, urinary cortisone levels decreased and the cortisol:cortisone ratio increased, indicating that CBX inhibited 11beta-HSD activity that metabolizes cortisol to cortisone. The complete lack of effect of CBX on the renin-aldosterone system in multisystem PHA patients indicates that CBX does not exert an effect via mineralocorticoid (MR) or glucocorticoid receptors. Examination of the structure and expression of the MR gene by Southern blot analysis and polymerase chain reaction (PCR) showed no abnormality. Whereas multiple PHA results from a spectrum of mutations in the mineralocorticoid activated epithelial sodium channel subunits, the genetic basis of renal PHA is still unknown. The response to CBX suggests that there is at least a partly functional MR in renal PHA patients.