Primary Gonadal Failure Research Articles

Genitourinary tract problems encountered in human immunodeficiency virus (HIV) infection and/or acquired immunodeficiency syndrome (AIDS) – a review of the literature

Background. Acquired immunodeficiency syndrome (AIDS) affects all organs of the genitourinary tract. In view of this, clinicians need to be aware of the ways in which AIDS affects each of these organs. Aim. The aim of this article is to review the literature regarding human immunodeficiency virus (HIV) infections and/or AIDS and its impact on the genitourinary tract. Methods. An internet search was carried out to document the reported associations between HIV infection or AIDS and the urinary tract. The search engines used were Google, Google Scholar and PubMed. Scrutiny of manuscripts which discussed in detail the association between HIV infection or AIDS and the organs of the genitourinary tract formed the basis for the review. Results. The organs of the genitourinary tract may be affected by AIDS in a number of ways, as follows: Urethra A number of patients infected with HIV or suffering from AIDS develop dysuria and urinary frequency as a result of cytomegalovirus infection. Other patients may develop B- or T-cell lymphoma involving the urethra. Prostate Opportunistic infections of the prostate gland may be encountered. Scrotum Atypical organisms associated with Fournier's gangrene may be encountered. Epididymis Opportunistic infections of the epididymis may occur. Testis Opportunistic infections of the testis, testicular atrophy and hypogonadism have been reported. Penis Kaposi's sarcoma and squamous cell carcinoma of the penis have been reported. Bladder Voiding dysfunction and acute retention of urine may develop. Urodynamics may show areflexia, hyporeflexia or hyperreflexia. Ureter Renal colic and ureteric obstruction may result from the deposition of concrements of antiretroviral drugs in the ureter. Kidney Structural renal problems including opportunistic infections, tumours and nephropathy may develop. Functional renal problems may include hyponatraemia, hypokalaemia and acute renal failure. Sexual function Primary or secondary gonadal failure in the HIV-infected patient may result in impotence. Malignancies Kaposi's sarcoma, non-Hodgkin's lymphoma and squamous cell carcinoma may develop. Obstruction of the upper urinary tract may necessitate creation of a nephrostomy. Conclusions A number of genitourinary problems have documented associations with HIV infection and AIDS, including opportunistic infections of genitourinary tract organs; functional and structural renal problems; tumours of the penis, bladder and other organs of the genitourinary tract; voiding problems including urinary retention; ureteric obstruction; and impotence.

Male hypogonadism: an extended classification based on a developmental, endocrine physiology‐based approach

Normal testicular physiology results from the integrated function of the tubular and interstitial compartments. Serum markers of interstitial tissue function are testosterone and insulin-like factor 3 (INSL3), whereas tubular function can be assessed by sperm count, morphology and motility, and serum anti-Müllerian hormone (AMH) and inhibin B. The classical definition of male hypogonadism refers to testicular failure associated with androgen deficiency, without considering potential deficiencies in germ and Sertoli cells. Furthermore, the classical definition does not consider the fact that low basal serum testosterone cannot be equated to hypogonadism in childhood, because Leydig cells are normally quiescent. A broader clinical definition of hypogonadism that could be applied to male patients in different periods of life requires a comprehensive consideration of the physiology of the hypothalamic-pituitary-testicular axis and its disturbances along development. Here we propose an extended classification of male hypogonadism based on the pathophysiology of the hypothalamic-pituitary-testicular axis in different periods of life. The clinical and biochemical features of male hypogonadism vary according to the following: (i) the level of the hypothalamic-pituitary-testicular axis primarily affected: central, primary or combined; (ii) the testicular cell population initially impaired: whole testis dysfunction or dissociated testicular dysfunction, and: (iii) the period of life when the gonadal function begins to fail: foetal-onset or postnatal-onset. The evaluation of basal testicular function in infancy and childhood relies mainly on the assessment of Sertoli cell markers (AMH and inhibin B). Hypergonadotropism should not be considered a sine qua non condition for the diagnosis of primary hypogonadism in childhood. Finally, the lack of elevation of gonadotropins in adolescents or adults with primary gonadal failure is indicative of a combined hypogonadism involving the gonads and the hypothalamic-pituitary axis.

Factors Influencing Outcome and Incidence of Late Complications in Children who Underwent Allogeneic Hematopoietic Stem Cell Transplantation for Hemoglobinopathy

Background: Hematopoietic stem cell transplantation (HSCT) remains the only potentially curative treatment for severe hemoglobinopathy (HGP). Late complications (LCs) are all events occurring beyond two years post-HSCT. We retrospectively analyzed prevalence, factors influencing occurrence, and prognosis of LCs post-HSCT for HGP. Patients and Methods: Between 2000 and 2011, 47 patients (21 males, 26 females; 43 with beta thalassemia major, four with sickle cell disease) who had survived more than two years post-HSCT for HGP were retrospectively reviewed. Mean age at HSCT was 7.7 years (1.1–32 years); mean follow-up was 7.1 years (2–11.6 years); 11 patients were splenectomized; mean ferritin level was 3022 ng/mL (350–10900); and seven patients underwent a second HSCT. Results: Endocrinological complications were observed with primary gonadal failure in 16/20 mature females and 4/11 mature males, in five patients with primary hypothyroidism and in four with insulin-dependent diabetes mellitus (DM). Skeletal complications were observed in 10 with secondary osteoporosis; 22 patients had elevated transaminase levels; two had hepatitis B reactivation. Neurological, cardiac and ocular manifestations were relatively rare. A higher incidence of LCs was observed in splenectomized than in nonsplenectomized patients: cGVHD −64% versus 13% (P = .003); endocrine abnormalities –91% versus 30.5%, (P = .001); elevated transaminase levels −73% versus 33% (P = .043); mortality –18% versus 2.7% (NS). Conclusions: LCs post-HSCT for HGP are common and heterogeneous. Etiology is multifactorial with iron overload (IO), class, splenectomy, age, chronic GVHD, and corticosteroid (CS) treatment. Our data may help build follow-up guidelines to limit, detect, and treat any LCs and improve quality of life.

The Physiology of Puberty and its Disorders

Puberty is a complex process of developmental change regulated by multiple genetic and endocrine controls. Abnormal pubertal development (both precocious and delayed puberty) can cause significant distress to the patient and may in some instances be a sign of life-threatening pathology. Delayed puberty is often due to constitutional delay of growth and puberty, but will also occur in cases of primary gonadal failure and in patients with disorders leading to diminished gonadotropin levels (ie, central nervous system [CNS] tumors). Precocious puberty may occur due to CNS disorders, certain genetic disorders, ectopic gonadotropin secretion or autonomous sex steroid secretion. Treatment is directed toward the underlying pathology, and may include agents to either stimulate or block pubertal development. Health care providers require knowledge of the normal onset of timing and rate of progression of puberty, and must be able to identify patients with abnormal pubertal development, as well as initiate the appropriate laboratory workup.

Impact of Taenia solium neurocysticercosis upon endocrine status and its relation with immuno-inflammatory parameters

Neurocysticercosis (NC) is a parasitic disease caused by the infiltration of the larval stage of Taenia solium in the central nervous system. Clinical presentations are heterogeneous and particularly depend, on the age and gender of the host. We designed a clinical study to evaluate the hormonal changes associated with neurocysticercosis and the relationships between disease heterogeneity, endocrine and immunological status. A total of 50 patients and 22 healthy subjects were included. A precise clinical and radiological description of disease for each patient was recorded. A broad hormonal profile was assessed for each participant and, in a sub-group of patients, immunological features were also evaluated. Compared with controls, all patients had lower dehydroepiandrosterone (DHEA) concentration; male patients also had lower concentrations of 17β-estradiol and higher concentrations of luteinising hormone (LH). In the clinically severe patients, lower concentrations of progesterone and androstenedione were found in women. Higher concentrations of follicle stimulating hormone (FSH) and lower concentrations of testosterone were found in men when compared with the less clinically severe patients. Significant correlations were found between estradiol and IL-10 in male patients, and between dehydroepiandrosterone (DHEA) and IL-1β, and androstenedione and IL-17 in female patients. To our knowledge the present study constitutes the first demonstration that the presence of T. solium larvae in the central nervous system can modify the host environment by the induction of endocrine and immunological changes. These results provide a stimulating background to analyse the repercussions of these changes on the course of the disease and on patient reproductive health.

Testicular Failure in Boys with Prader-Willi Syndrome: Longitudinal Studies of Reproductive Hormones

The pathophysiology of hypogonadism in boys with Prader-Willi Syndrome (PWS) remains uncertain. Several reports described hypogonadotropic hypogonadism, some reported primary gonadal failure, and others a combination of both. The aim of the study was to evaluate gonadal function over time in boys with PWS and the effect of GH treatment. We made a longitudinal assessment of inhibin B, FSH, testosterone, and LH levels in prepubertal boys and male adolescents with PWS. We studied 68 boys participating in the Dutch PWS Cohort study. Serum inhibin B, FSH, LH, and testosterone levels were compared with reference values. Boys with PWS had normal inhibin B levels between 6 months and 10 yr of age, but after onset of puberty, inhibin B levels declined to less than the 5th percentile, and FSH levels increased to more than the 95th percentile. Two years after the onset of puberty and in young adults, inhibin B levels were significantly lower (P=0.008 and P<0.0001), and FSH levels were significantly higher (P=0.034 and P<0.0001) than at onset of puberty. Testosterone levels increased but remained below the 5th percentile, and LH levels increased but not above the 95th percentile. Age showed a significant correlation with inhibin B levels (r=-0.31; P=0.001) after 9 yr of age. GH treatment had no significant effect on inhibin B levels. Our study indicates that the majority of male patients with PWS have primary testicular failure, which becomes apparent after onset of puberty. Hypogonadotropic hypogonadism did not appear to be the main reason of hypogonadism in most boys.

Persistent primary hypogonadism associated with anabolic steroid abuse

To report a case of primary gonadal failure due to the chronic abuse of anabolic steroids used for bodybuilding. Case report. Department of Diabetes and Endocrinology, Morriston Hospital, Swansea, Wales, United Kingdom. A 40-year-old man. None. Clinical symptoms, levels of serum T, FSH, and LH. Primary gonadal failure resulting from anabolic steroid use. We describe a case of initially secondary gonadal failure resulting from anabolic steroid use with subsequent primary gonadal failure and infertility. This case adds to the current literature and illustrates that the side effects of anabolic steroids can be prolonged and irreversible.

Combined Central Precocious Puberty and Primary Gonadal Failure after Treatment of Childhood Malignancy in Two Boys: A Diagnostic and Therapeutic Conundrum

Central precocious puberty and primary gonadal failure are known sequelae of childhood cancer or its treatment. Here we report two boys with coexistent central precocious puberty and primary gonadal failure after treatment for childhood malignancies.

Evaluation of the endocrine functions in dystrophia myotonica

Investigation of several endocrine functions was performed in seven patients with dystrophia myotonica (DM). All patients had hyperinsulinemia. Whereas the four female patients had normal pituitary-gonadal function, all three male patients presented evidence of a primary gonadal failure. Thyroid function was normal in all patients. Four patients displayed abnormal diurnal variations of cortisol secretion. Basal prolactin levels were elevated in three patients, one of whom also had consistently elevated levels of growth hormone. The investigation adds some new evidence of neuroendocrine dysfunction at the hypothalamic level in DM.

Indications for familial screening and gonadectomy in patients with 46,XY gonadal dysgenesis

The genetic aberration causing 46,XY gonadal dysgenesis, or Swyer syndrome, results in the complete sex reversal of the affected individual— who has normal female external genitalia and Mullerian structures. A 15-year-old girl (patient 1) presented with primary amenorrhea and no breast development but Tanner stage 3 pubic hair development. Her endocrine profile suggested primary gonadal failure and cytogenetic analysis revealed a 46,XY karyotype. Laparoscopic gonadectomy revealed a rudimentary uterus with normal fallopian tubes and streak gonads bilaterally. Family history taking allowed identification of a maternal second cousin and a maternal great aunt who also had a 46,XY karyotype, suggesting X-

Endocrine dysfunction and parameters of the metabolic syndrome after bone marrow transplantation during childhood and adolescence

Endocrine dysfunction and parameters of metabolic syndrome were assessed in 91 patients aged 4.3-32.5 years who underwent allogeneic or autologous BMT in childhood. Final short stature, found in five of the 35 patients who attained final height, was associated with the underlying disease (specifically, Fanconi anemia) (P=0.0013), previous cranial irradiation (P=0.0007), type of conditioning irradiation (P<0.05) and allogeneic BMT (P=0.05). Growth hormone deficiency (n=10) was associated with previous cranial irradiation (P<0.005) and conditioning total body irradiation (P<0.001). Twelve patients had primary hypothyroidism, one had hyperthyroidism and one papillary thyroid carcinoma. Hypothyroidism was associated with neck/mediastinal (P<0.005) and conditioning irradiation (P<0.05). Primary gonadal failure was found in 24 of the mature patients (62.5% females). Hypogonadism was associated with the underlying disease (especially hematological malignancies) (P<0.05), pretransplant treatment (P<0.05), irradiation conditioning (P<0.001), older age (P<0.005) and advanced pubertal stage at BMT (P<0.05). Obesity (body mass index >2 s.d.) was found in 4.4% and type II diabetes and impaired glucose tolerance in 3.3% each. Dyslipidemia was found in 27.9% of the 43 patients tested. These findings emphasize the need for long-term follow-up of endocrine and metabolic parameters in young patients after BMT in order to offer proper treatment and improve quality of life.

β-Adrenergic Hyperresponsiveness in Compensated Hypothyroidism Associated with Down Syndrome

Although compensated hypothyroidism (CH) is the most common thyroid impairment in Down syndrome (DS), its pathogenesis remains elusive. Because primary gonadal failure is another DS-associated endocrinopathy, we hypothesized that an impaired signal-transduction pathway shared by several organs may provide a unifying explanation for both endocrinopathies. We assessed two possible transduction-pathway components associated with CH in DS: the G-protein adenylate-cyclase (AC) system and beta-adrenergic responsiveness, previously reported to be enhanced in DS fibroblasts. Twenty-one DS patients and 14 control subjects were studied. Peripheral mononuclear cells (PMCs) were incubated with G-protein modulators [prostaglandin E1 (PGE1) and cholera toxin (CTx)], an AC stimulator (forskolin), and a beta-adrenergic agonist (isoproterenol), and cAMP levels were determined. All participants had normal plasma thyroid hormone levels, but 11 of the DS patients had elevated TSH levels (hTSH), whereas in the 10 others, they were normal (nTSH). cAMP levels in response to forskolin, PGE1, and CTx were similar in all groups, whereas isoproterenol-stimulated cAMP levels were significantly higher in the hTSH group than in the nTSH group and control subjects (45 +/- 30 versus 22 +/- 9 and 21 +/- 9 pmol . 10(6) cells(-1) . 10 min(-1), respectively; p = 0.02). Four patients in the DS hTSH subgroup had impaired sexual development. We found hyperresponsiveness of PMCs to a beta-adrenergic agonist in a subgroup of DS patients with CH. If this observation is applicable to the thyroid gland, then it may reflect a mechanism in which negative effects on cell growth or responsiveness to TSH lead to CH.

Endocrine complications of high-dose therapy with stem cell transplantation.

Evaluations of endocrine function following hematopoietic cell transplantation demonstrate that the endocrine function abnormalities observed are related to the type of transplant preparative regimen received. Children given high dose cyclophosphamide (CY) only have normal thyroid function, normal growth and development. Children who received a busulfan (BU) plus CY preparative regimen usually have normal thyroid function, normal prepubertal growth, delayed or absent pubertal development, and blunted post-pubertal growth. Recipients of preparative regimens containing total body irradiation may be anticipated to have some thyroid dysfunction, impaired growth rates and delayed or absent pubertal development. Post-pubertal teens and young adults are likely to have gonadal function recover if they received a preparative regimen with CY only but are likely to have primary gonadal failure if they received a preparative regimen with BU or total body irradiation. Individuals whose gonadal function becomes normal have become parents of normal children. All patients who receive a marrow transplant should be followed long-term for development of endocrine function abnormalities.

The Early Dehydroepiandrosterone Sulfate Rise of Adrenarche and the Delay of Pubarche Indicate Primary Ovarian Failure in Turner Syndrome

Pubarche without thelarche has been taken as clinical evidence that adrenarche is independent of gonadarche in females. This study examines whether the course of adrenarche [rise of serum dehydroepiandrosterone sulfate (DHEAS)] and pubarche (Tanner stage PH2) is independent from ovarian function. Serum DHEAS levels (n = 867) were longitudinally measured in 111 girls with Turner syndrome between 1990 and 2002. Of these, 22 had spontaneous puberty onset (Tanner stage B2), and 45 had primary ovarian failure (POF). Serum DHEAS levels were assayed by chemiluminescence and compared with those of healthy girls (n = 322; age range, 3-17 yr in both groups). Between the ages of 7 and 17 yr, girls with Turner syndrome had significantly higher age-related DHEAS levels than normal girls (P </= 0.02). Moreover, in the 9- to 15-yr-old girls, DHEAS levels were significantly higher in girls with Turner syndrome and POF than in Turner syndrome girls with spontaneous puberty onset (P </= 0.02). This discrepancy was caused by an earlier adrenarche (DHEAS levels reaching 1.1 micro mol/liter) in Turner syndrome girls with POF, which occurred at a median age of 8.3 yr (80% confidence interval, 6.5-10.4 yr) vs. 10.5 yr (8.6-12.2) and 11.0 yr (8.9-12.6) in Turner syndrome girls with spontaneous puberty onset and normal girls, respectively (P = 0.003). In contrast, pubarche was delayed in Turner syndrome girls with POF [median age, 13.0 yr (80% confidence interval, 10.6-15.0) vs. 11.9 yr (10.5-13.2) in Turner syndrome girls with spontaneous puberty onset (P = 0.02) and 11.6 yr (10.6-12.5) in normal girls]. Primary gonadal failure in Turner syndrome is associated with an earlier onset of adrenarche, but delayed pubarche. These data demonstrate that normal timing of adrenarche is dependent on gonadal function and suggest that normal pubarche is the clinical manifestation of the ovarian conversion of DHEAS to active androgens.

Clomiphene increases free testosterone levels in men with both secondary hypogonadism and erectile dysfunction: who does and does not benefit?

Secondary hypogonadism is more common than primary gonadal failure and is seen in chronic and acute illnesses. Although testosterone has a role in erections, its importance in erectile dysfunction (ED) has been controversial. Hypogonadism produced by functional suppression of pituitary gonadotropins has been shown to correct with clomiphene citrate, but with a modest effect on sexual function. We wondered if longer treatment would produce improved results. A total of 178 men with secondary hypogonadism and ED received clomiphene citrate for 4 months. Sexual function improved in 75%, with no change in 25%, while significant increases in luteinizing hormone (P<0.001) and free testosterone (P<0.001) occurred in all patients. Multivariable analysis showed that responses decreased significantly with aging (P<0.05). Decreased responses also occurred in men with diabetes, hypertension, coronary artery disease, and multiple medication use. Since these conditions are more prevalent with aging, chronic disease may be a more important determinant of sexual dysfunction. Men with anxiety-related disorders responded better to normalization of testosterone. Assessment of androgen status should be accomplished in all men with ED. For those with lower than normal age-matched levels of testosterone treatment directed at normalizing testosterone with clomiphene citrate is a viable alternative to giving androgen supplements.

Chronic graft-versus-host disease and late effects after hematopoietic stem cell transplantation.

Late effects following HSCT are related to either the transplant process or to the transplant preparative regimen. Problems related to the transplant process include delayed recovery of the immune system and chronic GVHD. Chronic GVHD presents between 3-14 months post-HSCT in approximately 20% of matched sibling transplants and 40% of matched unrelated donor recipients. Most commonly involved sites are skin, mouth, liver, gastrointestinal tract, and eye. Patients with platelet count < 100,000/ml and receiving cortocosteroid therapy at day 80 with any clinical manifestations of chronic GVHD require prolonged immune suppressive therapy with prednisone, cyclosporine +/- other agents. Treatment should be administered until all clinical and pathological signs and symptoms of chronic GVHD have resolved which may take one to several years. Problems related to the transplant preparative regimen include those involving the endocrine system, eyes, lungs, bone, and development of secondary malignancies. Endocrine deficiencies include growth failure with growth hormone (GH) deficiency, overt hypothyroidism, primary gonadal failure, Type 1 or Type 2 diabetes, and exocrine pancreatic insufficiency. These problems develop at any time post-HSCT, but usually occur within the first few years and should be treated with appropriate hormone supplementation. Eye problems are primarily related to development of cateracts secondary to total body irradiation (TBI) or prolonged corticosteroid use. Cateracts developing after fractionated frequently do not require removal. Pulmonary problems may be due to bronchiolitis obliterans (BO) or to restrictive lung disease. BO may be associated with chronic GVHD and may respond to chronic GVHD therapy. Restrictive lung disease does not occur for many years after HSCT. There is not therapy for this problem. Development of decreased bone mineral density (BMD) is related to GH deficiency and/or corticosteroid therapy. Treatment includes withdrawal of corticosteroids, administration of GH and calcium, Vitamin D and antiresorptive agents. All malignant disease survivors are at risk for development of secondary malignancies, including survivors of HSCT. Recipients of TBI are at highest risk as are children. All pediatric and adult survivors of HSCT should be followed for their life-time for development of delayed effects of transplantation.

Delayed puberty.

Delayed puberty.

Recent advances in the molecular genetics of congenital and acquired primary adrenocortical failure.

IntroductionIn recent years there have been many advances in ourunderstanding of the molecular pathogenesis of both congenitaland acquired adrenocortical failure (autoimmune or otherwise).As well as providing some fascinating insights into adrenalgland development and steroid hormone biosynthesis, therecognition of these various distinct disorders, either at aclinical or molecular genetic level, often has implications forthe management of the patient and their immediate family. In thispaper, we review the salient clinical and molecular features of thevarious causes of primary adrenocortical failure (Table 1).Genetics of autoimmune Addison’s diseaseAutoimmune Addison’s disease (AAD) is a chronic disorder ofthe adrenal gland, characterized by insufficiency of adrenocor-tical hormones due to autoimmune destruction of steroidogenicadrenocortical cells (Oelkers, 1996). The cytochrome P450enzymes involved in steroidogenesis, including 21-hydroxylase(Baumann-Antczak et al., 1992; Winqvist et al., 1992), 17-hydroxylase (Krohn et al., 1992) and side chain cleavageenzyme (Winqvist et al., 1993) have been identified as primaryautoantigens in AAD. With the overall decrease in theprevalence of tuberculosis, AAD has emerged as the mostcommon cause of primary adrenal failure in developedcountries (Nerup, 1974; Kong & Jeffcoate, 1994). Nevertheless,AAD is a relatively rare endocrinopathy; recent epidemiologi-cal studies showing an estimated prevalence in the generalEuropean population of about 100 per million (Kong J Laureti et al., 1999).The results of human leucocyte antigen (HLA) typing, takentogether with the clinical heterogeneity of presentation anddifferent modes of inheritance, have suggested distinctpathogenic bases for different forms of AAD. Thus, AADmay occur in isolation, as a manifestation of the autoimmunepolyendocrinopathy type 1 syndrome (APS1), or as part of theautoimmune polyendocrinopathy type 2 (APS2) syndrome(Table 1) (Spinner et al., 1968; Neufeld et al., 1981; Maclaren& Riley, 1986).Autoimmune polyendocrinopathy type 1 syndrome: amonogenic autoimmune disorderIn the autoimmune polyendocrinopathy type 1 (APS1)syndrome, which is also known as the autoimmune poly-endocrinopathy, candidiasis and ectodermal dystrophy(APECED) syndrome, AAD occurs in association withautoimmune hypoparathyroidism, chronic mucocutaneous can-didiasis and other organ-specific autoimmune disorders. Theseinclude type 1 diabetes, primary gonadal failure, perniciousanaemia, chronic active hepatitis and hypothyroidism (Neufeldet al., 1981; Ahonen et al., 1990). The age of onset of AAD inAPS1 is typically between 11 and 15years, although othermanifestations of APS1 (e.g. hypoparathyroidism and candi-diasis) are likely to present at an earlier age. APS1 is amonogenic disorder with autosomal recessive inheritance,affecting both sexes with equal prevalence (Ahonen, 1985),and is rare in most populations. However, because of foundereffects, it is relatively common in the Finnish population andIranian Jews with estimated prevalences of 1/25000 and 1/9000, respectively (Ahonen, 1985; Zlotogora & Shapiro, 1992).Initial genetic studies of APS1 focused on HLA, and noassociation of this disorder with any specific HLA haplotypehas been found (Neufeld et al., 1981; Maclaren & Riley, 1986;Aaltonen et al., 1993; Huang et al., 1996). The gene underlyingAPS1 was subsequently localized on chromosome 21q22 bylinkage analysis (Aaltonen et al., 1994) and identified bypositional cloning (Finnish-German APECED consortium,1997; Nagamine et al., 1997). This gene, designated auto-immune regulator-1 (AIRE-1), encodes a 545 amino acidprotein that has two plant homeodomain (PHD)-type zinc-finger motifs, suggesting a role as a transcription factor(Finnish-German APECED consortium, 1997; Nagamine etal., 1997). AIRE-1 mRNA is expressed in lymphoid tissuesincluding thymus, lymph node and spleen, and possibly also inother tissues including the adrenal cortex (Finnish-GermanAPECED consortium, 1997; Nagamine et al., 1997), whichsuggests that it may have an important role in the developmentof a normal immune response.

The Effect of Short-Term Treatment With Micronized Estradiol on Bone Turnover and Gonadotrophins in Older Men

Evidence for the role of estrogen in male bone metabolism has been confirmed by studies on a man with a genetic defect in the estrogen receptor as well as men with aromatase defects. All exhibited tall stature, delayed epiphysial closure, decreased bone density and increased bone turnover. Estrogen is likely to affect bone turnover in men throughout life; therefore, we hypothesized that older men would show decreased bone resorption in response to estrogen therapy. To test our hypothesis, fourteen community-dwelling men with osteopenia of the femoral neck were treated for 9 weeks with micronized estradiol, 1 mg/d, a dose which is effective in postmenopausal women. Each subject served as his own control. Markers of bone resorption, N-terminal collagen crosslinks (NTX) and C-terminal collagen crosslinks (CTX) and markers of bone formation, osteocalcin (OC) and bone specific alkaline phosphatase (BSAP) were measured every 3 weeks during a 9-week treatment period and 9 weeks post-treatment. Sex hormones, gonadotrophins and calciotropic hormones were measured at baseline, 9 weeks on treatment and 9 weeks post- treatment. After 9 weeks of treatment, estradiol and estrone levels increased significantly by greater than 6-fold and 15-fold, respectively. SHBG levels increased significantly by 17%. Testosterone and free testosterone levels decreased significantly by 27% and 34%, respectively. Markers of bone resorption showed wide variation at baseline and while on treatment. There was no correlation between changes in bone markers and changes in estrogen levels. During treatment, 11 patients showed a decrease of NTX or CTX, but three showed an increase. These three and one other subject had high initial levels of FSH and LH, suggesting some degree of primary gonadal failure, which decreased during estrogen therapy. Thus, the change in NTX (and CTX) after 9 weeks of E2 treatment was correlated with initial FSH (r= -.66, p= .01) and LH (r= -.73, p= .003) values. In addition, the largest decrease in free testosterone at 9 weeks was correlated with the higher values for NTX, CTX and BAP (r=-0.66, -0.68, -0.70 respectively; p≤.01 for each of the markers). Treatment was generally well tolerated. Side effects of treatment were minimal, and included breast tenderness and decreased libido which reversed after treatment. We conclude that it is feasible to give low dose estrogen to healthy older men, but that the effects on bone turnover are not consistent. Changes in central feedback and in endogenous sex hormone production may alter the response of bone turnover to exogenous estrogen in this population.

An unusual case of pseudodicentric Xq and one possible mechanism

Structural abnormalities of the X chromosome are relatively common with isochromosome Xq being the most common. While isochromosome for Xp has been reported, its existence is questionable since true isochromosome Xp lacks the inactivation center and thus is presumed to be non-viable. Most of these cases are in fact believed to be pseudodicentric (having one active and one inactive centromere) and contain at least one inactivation center. We report an 18 year old female referred for primary gonadal failure (elevated FSH and LH; decreased estradiol). Cytogenetics revealed a 46,X,psu dic(X)(q24) karyotype suggesting trisomy for Xp and proximal Xq and monosomy for Xq distal to band q24. Fluorescent in situ hybridization (FISH) analysis using whole chromosome paint and XIST probes confirmed a structurally abnormal dicentric X chromosome containing two inactivation centers. Additional clinical history included oligoammenorrhea with menarche at age 12 and insulin dependent diabetes mellitus with onset at 14-15 years of age. No significant Turner stigmata were noted which may be attributable, in part, to an indeterminate X inactivation pattern. Mechanisms for the formation of pseudodicentric X chromosomes have been hypothetical thus far. One proposed mechanism is a U-type exchange between two chromatids or chromosomes following a break in each at a homologous site. This repair process would result in a dicentric inverted duplication or dicentric X chromosome. We propose another mechanism and suggest that the genetic constitution may have begun as trisomy X. Breaks in two of the X chromosomes at band q24 with subsequent fusion of the centric fragments would result in a pseudodicentric X chromosome. The remaining acentric fragments would be lost in continued cell division. Further investigation by microdissecting the dicentric X chromosome may help in understanding other atypical cytogenetic mechanisms for dicentric chromosome formation. These studies could determine whether the dicentric centromeres originated from homologous X chromosomes or are identical via duplication.