Mixed gonadal dysgenesis: a syndrome of broad clinical, cytogenetic and histopathologic spectrum.

Mixed gonadal dysgenesis (MGD) is an abnormality of sexual differentiation (ASD), which encompasses an heterogeneous group of different gonadal and phenotypic abnormalities. This study describes the main clinical features found in 16 patients with MGD, relating the clinical presentation with cytogenetic evaluation and histopathological findings. For purpose of this study, MGD was considered in those patients who fulfilled the following diagnostic criteria: 1) müllerian and/or wolfflan derivatives; 2) any of the following gonadal characteristics: a) bilateral intrabdominal or scrotal immature testicular tissue; b) intrabdominal or scrotal immature testicular tissue with contralateral streak gonad. Patients were selected from an ASD study which was carried out in Medical Genetic Unit of University of Zulia (UGM-LUZ), Maracaibo, Venezuela, from 1980 to 1997. The following information was extracted from the medical history at UGM-LUZ: age, gender which patient was reared, clinical presentation, cytogenetic evaluation, laparoscopic findings and gonadal biopsy. Sixteen patients fulfilled the diagnostic criteria and ranged in age from 1.2 to 39.4 years with an average of 12.65 years. Only 5 patients were reared as males. Twelve patients consulted for genital ambiguity. Chromosomal evaluation was as following: 8 patients with 45,X/46,XY mosaicism: 5 had a 46,XY normal male karyotype and the remaining patients: 46,XX; 46,XX/46,XY and 45,X/46,Xi(Xq) karyotypes, respectively. All patients showed müllerian derivatives and occasionally wolffian derivatives. Gonadal tumors were present in 2 patients. Molecular studies of genes that govern gonadal development are necessary for a better understanding of the wide heterogeneity present in MGD.     

Factors attenuating growth promoting effect of growth hormone therapy for Turner's syndrome

Nine patients with Turner's syndrome aged 7 to 13 years were treated with recombinant human growth hormone (hGH) at a dose of 0.5 or 1.0 U/kg/w for 1 year. In five of them the growth rate was accelerated from 3.3 +/- 0.6 (SD) to 6.5 +/- 0.5 cm/y (group A), whereas 4 had a reduced rate of growth promotion (3.4 +/- 0.3 to 4.6 +/- 0.4 cm/y) (group B). Analysis of factors affecting growth response to hGH revealed 3 major parameters: (1) age of initiating hGH therapy (A, 9.5 +/- 2.1 vs B, 13.3 +/- 0.4 yrs, P less than 0.01), (2) basal LH (A, 3.2 +/- 2.4 vs, B, 44.9 +/- 17.8 mIU/ml, P less than 0.001) and FSH levels (A, 14.7 +/- 15.4 vs B, 131 +/- 49 mIU/ml; P less than 0.01) and (3) somatomedin-C (SM-C) producing capacity: coefficient of correlation to growth rate, r = 0.80, P less than 0.01). No remarkable changes were observed in the results of glucose tolerance, thyroid state, calcium metabolism and liver function tests. These results indicate that patient's age is the most crucial factor in effective treatment with hGH, and in adolescent girls, gonadal failure with a limited increase in SM-C production attenuates the growth promoting potency of hGH.     

A 46,XY female DSD patient with bilateral gonadoblastoma, a novel SRY missense mutation combined with a WT1 KTS splice-site mutation

Patients with Disorders of Sex Development (DSD), especially those with gonadal dysgenesis and hypovirilization are at risk of developing malignant type II germ cell tumors/cancer (GCC) (seminoma/dysgerminoma and nonseminoma), with either carcinoma in situ (CIS) or gonadoblastoma (GB) as precursor lesion. In 10-15% of 46,XY gonadal dysgenesis cases (i.e., Swyer syndrome), SRY mutations, residing in the HMG (High Mobility Group) domain, are found to affect nuclear transport or binding to and bending of DNA. Frasier syndrome (FS) is characterized by gonadal dysgenesis with a high risk for development of GB as well as chronic renal failure in early adulthood, and is known to arise from a splice site mutation in intron 9 of the Wilms' tumor 1 gene (WT1). Mutations in SRY as well as WT1 can lead to diminished expression and function of SRY, resulting in sub-optimal SOX9 expression, Sertoli cell formation and subsequent lack of proper testicular development. Embryonic germ cells residing in this unfavourable micro-environment have an increased risk for malignant transformation. Here a unique case of a phenotypically normal female (age 22 years) is reported, presenting with primary amenorrhoea, later diagnosed as hypergonadotropic hypogonadism on the basis of 46,XY gonadal dygenesis with a novel missense mutation in SRY. Functional in vitro studies showed no convincing protein malfunctioning. Laparoscopic examination revealed streak ovaries and a normal, but small, uterus. Pathological examination demonstrated bilateral GB and dysgerminoma, confirmed by immunohistochemistry. Occurrence of a delayed progressive kidney failure (focal segmental glomerular sclerosis) triggered analysis of WT1, revealing a pathogenic splice-site mutation in intron 9. Analysis of the SRY gene in an additional five FS cases did not reveal any mutations. The case presented shows the importance of multi-gene based diagnosis of DSD patients, allowing early diagnosis and treatment, thus preventing putative development of an invasive cancer.     

Activin induces x-zone apoptosis that inhibits luteinizing hormone-dependent adrenocortical tumor formation in inhibin-deficient mice

Inhibin and activin are members of the transforming growth factor beta (TGF-beta) family of ligands produced and secreted primarily by the gonads and adrenals. Inhibin-null (INH(-/-)) mice develop gonadal tumors and-when gonadectomized-adrenocortical carcinoma. The mechanisms leading to adrenal tumorigenesis have been proposed to involve the lack of a gonadal factor and/or a compensatory increase in gonadotropins. In order to achieve elevation of gonadotropins without the concomitant loss of a gonadal hormone, we crossed INH(-/-) mice with a transgenic mouse strain that has chronically elevated luteinizing hormone (LH) levels (LH-CTP). Compound INH(-/-)-LH-CTP mice die within 6 weeks of age from severe cancer cachexia induced by large, activin-secreting ovarian tumors. Unexpectedly, INH(-/-)-LH-CTP mice not only fail to develop adrenal tumors but have smaller adrenals, with a regressed x zone, indicating that elevated LH levels are not sufficient to induce adrenal tumor formation. However, following gonadectomy, INH(-/-)-LH-CTP mice develop large, sex steroid-producing adrenal tumors that arise from the x zone, indicating a growth-promoting effect of high levels of LH on the adrenal cortex in the absence of ovarian tumors. In addition, in vivo and in vitro data indicate that activin induces apoptosis specifically in the adrenal x zone. The restricted expression of activin receptor subunits and Smad2 in cells of the adrenal x zone, together with the elevated activin levels in INH(-/-)-LH-CTP mice, supports the conclusion that activin inhibits adrenal tumor growth by inducing x-zone regression.     

The Cardiff Cervical Cytology Study: prevalence of cytological grades and initial histological findings.

Among 45 266 women in the Cardiff Cervical Cytology Survey the peak prevalence of suspicious or positive smears was 11.2/1000 at age 45-50 years and of dyskaryosis 10.2/1000 at age 25-29. A suspicious or positive cytological picture at prevalence testing was associated with occult or clinical invasion in 24% of cases, and only 4% of patients with suspicious or positive smears were normal histologically. When dyskaryosis was detected in the prevalence test 20% had carcinoma in situ or microinvasion and 3% had occult or clinically invasive carcinoma. One hundred and twenty-nine (51%) women with dyskaryotic smears did not have a biopsy initially (that is, within two years of the prevalence test), but they were followed up at regular intervals. Subsequently 15 of the 129 gave smears consistently dyskaryotic or worse cytologically and were subjected to biopsy. Of these, two showed dysplasia, 12 carcinoma in situ, and one clinically invasive carcinoma. These findings emphasise the need for repeat cytological or histological examination in any woman with evidence of dyskaryosis in a cervical smear.     

High incidence of hyperandrogenism-related clinical signs in patients with multiple sclerosis

A mild prevalence of multiple sclerosis (MS) is present in females (2:1). To elucidate the pathogenetic role of sex steroids on the disease, we studied 76 women affected by MS, compared to 50 healthy women (mean age +/- SD, 34.9 +/- 0.9 vs. 33.4 +/- 1.7 years). The menarche was at mean age of 12.3 +/- 0.2 vs. 12.4 +/- 0.2. Interval between menses was 28.0 +/- 0.3 vs 27.8 +/- 0.3 days, with duration of menstrual flow of 5.0 +/- 0.2 vs. 5.0 +/- 0.2 days. Oligo- or amenorrhea was present in 20% of patients and in 16% of controls. Oral contraceptives were assumed by 21% of patients and 34% of controls (n.s.). Premenstrual symptoms were found in 43% of patients and in 46% of controls (n.s.). The incidence of hyperandrogenism (greasy skin, acne and hirsutism), evaluated by a specific questionnaire, was higher and statistically significant in MS patients than in controls (28% vs. 10%, p<0.05). Further studies, including a complete clinical and laboratory evaluation of gonadal function, are necessary in order to clarify whether hyperandrogenism may influence MS disease activity.     

Incidence,trends, and risks of ectopic pregnancy in a population of women.

In a 20-year longitudinal study on ectopic pregnancy in a defined population of women aged 15-39 years the rate of ectopic pregnancy per 1000 diagnosed conceptions increased from 5.8 during 1960-4 to 11.1 during 1975-9. The mean annual incidence of ectopic pregnancy per 1000 women increased from 0.6 to 1.2 during the same period. The numbers of ectopic pregnancies per 1000 diagnosed conceptions increased with increasing age of the women and were 4.1, in the teenage group 6.9, in women aged 20-29 years, and 12.9 in women aged 30-39. Among 20- to 29-year-old sexually active women at risk of pregnancy who had never had acute salpingitis the rates of ectopic pregnancy per 100 woman-years were the same in those who did not use contraceptives as in those using non-medicated or copper-medicated intrauterine contraceptive devices (IUCDs; 0.3/100 woman years). The risk of an ectopic pregnancy increased sevenfold after acute salpingitis. These findings confirm the increased risk of ectopic pregnancy after salpingitis and suggest that the increase in the incidence of ectopic pregnancy in Lund from 1960 to 1979 was partly accounted for by the use of IUCDs.     

Fine structure of the early stages of spermatogenesis in the Pacific oyster, Crassostrea gigas (Mollusca, Bivalvia)

The aim of this study is to describe the early stages of spermatogenesis of the Pacific oyster Crassostrea gigas using both light and electron microscopy. The gonad is formed by gonadal tubules invaginated in a connective tissue constituting a storage tissue. Myoepithelial cells surround each gonadal tubule and are associated with an acellular matrix delimiting the outer part of the tubule, the inner part is composed by intragonadal somatic cells associated with germinal lineage. Two types of spermatogonia are identified, where type I spermatogonia (Spg I) are large, scarce and pale cells leaned against the base of the tubule (nuclear diameter: 5.5+/-0.5 microm). Type II spermatogonia (Spg II) are clustered and dark cells which appear smaller than type I (nuclear diameter: 4.3+/-0.3 microm). The aspect of nuage-like material in cytoplasm is described from pale spermatogonia to primary spermatocytes (nuclear diameter: pachytene 3.6+/-0.3 microm, diplotene 3.4+/-0.3 microm), while no structure related to a chromatoid body was observed in oyster spermatocytes and spermatids.     

The development of the reproductive organs of the male giraffe, Giraffa camelopardalis

The reproductive organs of the male giraffe differ little in morphology and histology from those of other ungulates. There is some indication that gonadal hypertrophy occurs in late fetal life. Spermatogenesis begins at 3-4 years of age and coincides with a rapid increase of testicular weight and seminiferous tubule diameter. In the fetal testis the main hormone is androsteredione (2.73 microgram/g) but in adult testes testosterone is predominant (less than 10.08 microgram/g) and delta' testosterone may also be present.     

Juvenile bisexuality in the red sea bream,Pagrus major

The histology of the gonad of the red sea bream,Pagrus major, was examined in order to study the early gonadal development, sexual maturation and sex ratio in a natural population. A total of 1,117 fish between the ages of 4 months and 8 years were examined. Gonads of 4-month-old fish were either sexually undifferentiated with a central cavity, or ovarian in form. Gonads of 12- and 18-month-old fish were ovaries or bisexual gonads, while those of 2-year-old fish were ovaries, bisexual gonads or testes. Fish aged between 3 and 8 years had ovaries or testes, except for a few bisexual gonads found in 3- and 4-year-old fish. The chronological appearance of females, hermaphrodites and males in that order, and histological evidence, suggested that the testis originates from the ovary via a bisexual gonad in the juvenile stage. The sex ratio of females to males at the age of 2 years and over was about 1:1, suggesting that hermaphroditic red sea bream appear in about 50% of the juvenile population. The sexual pattern in this species, therefore, is concluded to be gonochorism with a bisexual juvenile stage.     

Prevalence of carcinoma in situ of the testis in 207 oligozoospermic men from infertile couples: prospective study of testicular biopsies.

OBJECTIVE: To investigate the prevalence of carcinoma in situ of the testis in a group of oligozoospermic men from infertile couples. DESIGN: A consecutive group of oligozoospermic men from infertile couples were offered bilateral testicular biopsy. The observed prevalence of carcinoma in situ was compared with the expected prevalence of testicular cancer in a corresponding age matched population of Danish men, assuming all untreated cases of carcinoma in situ progress to tumour stage. This calculation was based on data from the Danish Cancer Registry. SUBJECTS: 207 men aged 18-50 years who had sperm density below 10 million/ml in two samples within the previous 2 years or sperm density below 20 million/ml in two samples within the previous 2 years and a history of cryptorchidism or one or two atrophic testicles (orchidometer volume less than 15 cm3), or both. INTERVENTIONS: Bilateral testicular biopsies. MAIN OUTCOME MEASURES: Carcinoma in situ in the biopsy specimen. RESULTS: No case of carcinoma in situ was found among the 207 men. The expected number in a normal age matched population of corresponding size was 0.8. CONCLUSIONS: There is no increase in risk of carcinoma in situ of the testis in moderately oligozoospermic men of couples referred because of infertility.     

Chemotherapy with doxorubicin in progressive medullary and thyroid carcinoma of the follicular epithelium.

Twenty-two patients (mean age 61) with metastasizing, progressive, nonradioiodine-accumulating thyroid carcinoma of the follicular epithelium were treated with doxorubicin between 2000 and 2005. Tumors were histologically classified as follicular in 15 patients (68%) and papillary in 7 patients (32%). In addition, nine patients (mean age 51 years) with medullary thyroid carcinoma were treated with doxorubicin between 1997 and 2005. Treatment consisted of doxorubicin: either 8 cycles of 15 mg/m2 weekly or 3 cycles of 60 mg/m2 every 3 weeks, repeated once, depending on response and side effects. The effect of therapy was evaluated by radiographic imaging, [18F] FDG-PET, and bone scans. In patients with papillary or follicular thyroid carcinoma, 5% had a partial regression over 6 months, 42% had stable disease for a median of 7 months (range: 1-22), and 53% had continuous progression established over 5 months (range: 1-11). Three patients died before completing chemotherapy. In patients with medullary thyroid carcinoma, 11% had a partial regression over 6 months followed by stable disease for 3 months, 11% had stable disease over 7 months, and 79% demonstrated progressive disease established over 5 months (range: 2-12). Doxorubicin can be a valid chemotherapy option, especially for advanced or metastatic thyroid carcinoma of the follicular epithelium.     

Salivary progesterone and luteal function in two low-fertility populations of Northeast Zaire

30 Ituri women (Zaire) -- 14 Efe and 16 Balese -- were targeted as subjects in this study designed to verify that, under field conditions, the salivary steroid method can reliably discern follicular and luteal levels of progesterone in normal menstrual cycles and to examine the hypothesis that infertility among these women is due to tubal factors. Findings of normal ovulatory function in fertile women would support the hypothesis; findings of abnormal gonadal function might either indicate a chronic endocrine imbalance or the short-term effects of nutritional and other stressors. All potential subjects ranged in age between 20-35 years, were involved in stable conjugal unions, had no nursing children, and reported either no births or none within the last 6 years. 25 women completed the study. The Boston field control subjects consisted of 18 volunteers ranging in age between 18-43 years. All reported a history of regular menstrual cycles and were nither using oral steroid contraceptives nor engaged in a regular exercise program. The African women had significantly lower luteal progesterone levels than did the Boston controls. Additionally, a significantly higher proportion of the African women failed to demonstrate clear luteal activity, suggesting that a higher rate of anovulation contributed to the low average luteal progesterone levels. The composite-cross-sectional profile for the Ituri Forest women suggests that the average luteal phase for this group was shorter than for the Boston controls. Further investigations need to determine whether gonadal dysfunction such as observed in this study is a regular feature of the reproductive physiology of women in the Ituri Forest, or whether it emerges only in periods of food shortage and significant weight loss. Gonorrhea may be the major cause of infertility in the Ituri region, but it is likely that other factors directly affecting gonadal function contributed to the observed pattern of low fertility. Clearly, the study illustrates the potential usefulness of salivary steroid assays.     

Annual cycles in moult, body mass, luteinizing hormone, prolactin and gonadal steroids during the development of sexual maturity in the White stork (Ciconia ciconia)

Annual variations in moult, body mass, and the plasma concentrations of luteinizing hormone, prolactin and the gonadal steroids, oestradiol and testosterone, were measured in captive White storks ( Ciconia ciconia ). Data were collected at approximately monthly intervals for 13 months on storks hatched over five successive years, the youngest ones being in their first, the oldest in their fifth, year of life.
Moulting of wing feathers occurred during the summer months, April through August. Young birds began to moult at least one month earlier, and replaced more wing feathers each year, than did three- to five-year-old birds. Body mass exhibited remarkably consistent annual cycles with minima of2–9-3-5 kg, during the summer months, and maxima of3–8-4-5 kg, during the winter months. Young males were heavier at all times of the year than young females, although this difference was gradually reduced to non-significant levels by four years of age. Luteinizing hormone, prolactin and the gonadal steroids, oestradiol and testosterone, exhibited annual cyclic changes, usually of a bi-modal nature. No major differences in hormone profiles, however, were found between any of the age groups. The phenomenon of deferred maturity in the stork does not parallel that of puberty found in many mammals.     

Comparison of breast carcinomas diagnosed in the 1980s with those diagnosed in the 1940s to 1960s.

OBJECTIVE--To find out if breast carcinomas diagnosed in the 1980s differ from those diagnosed a few decades ago. DESIGN--Retrospective comparative cohort study. SETTING--City of Turku, south western Finland. PATIENTS--439 patients with breast carcinoma diagnosed in 1945-65 with a median follow up of 27 years (95% of all those histologically diagnosed in Turku); and 370 patients with breast carcinoma diagnosed in 1980-4 with a median follow up of 6 years (94% of all those histologically diagnosed in Turku). MAIN OUTCOME MEASURES--Breast cancer incidence, mortality from breast cancer, age at diagnosis, stage of cancer, seven histological factors, DNA ploidy. RESULTS--Age adjusted incidence of breast cancer increased from 30.8/100,000 person years in 1953-7 to 62.2/100,000 in 1983-7; mortality in breast cancer increased from 16.7 to 17.2/100,000 person years. Survival of patients with stages II to IV (but not with stage I) improved. The mean age at diagnosis increased from 55.5 years in 1945-55 to 62.5 years in 1980-4 (p less than 0.0001); the proportion of patients with T0-1 carcinomas increased from 13% to 41% (p less than 0.0001) and with pN0 carcinomas from 43% to 55% (p = 0.003) from 1945-65 to 1980-4. There was no change in histological type or DNA ploidy of breast cancer, but in the 1980-4 cohort carcinomas were more often well differentiated, had lower mitotic counts and less nuclear pleomorphism, more often had a well defined tumour margin, and had less tumour necrosis. There was, however, no difference between the two cohorts in these histological characteristics except for tumour necrosis when they were compared in a multivariate log linear model at a given size of primary tumour. CONCLUSION--Improved survival with breast cancer can at least partially be explained by detection of increased numbers of small carcinomas with favourable histological characteristics.     

Epidemiological features of HIV infection among pregnant women in Makurdi, Benue State, Nigeria

Women in Benue State have for years had the highest HIV rate in the country, but because the sentinel surveys are anonymized and unlinked, not much is known about the socio-demographic, behavioural and other risk factors that predispose these women to the disease. The HIV/AIDS epidemic in Nigeria does not appear to be a single epidemic but rather multiple epidemics of varying magnitude and trends. This cross-sectional study was therefore carried out to identify the risk factors for HIV/AIDS among these women. A total of 404 consecutive consenting mothers enrolled at the booking clinic were followed up until delivery of their babies. They were interviewed using a semi-structured questionnaire and tested for HIV infection using an ELISA-based kit after obtaining informed consent. Mean age of the mothers was 26+/-6.1 years, 94.8% were married while 50.5% had at least secondary level education. Sixty-one (15.1%) mothers were HIV positive with mothers aged 15-24 years being responsible for 50.8% of all infection. Following bivariate analysis, being single, having a partner with low level of formal education, living in a rural location, being in a polygamous/multiple partner union, being a higher order polygamous wife, being married more than once and reporting a history of a sexually transmitted infection were significantly associated with HIV infection. Monogamous women who lived apart from their partners and women who had ever had blood transfusion were also more likely to be HIV positive. Following multivariate logistic regression, a young age of 15-24 years (multivariate OR=3.3, 95 % CI=1.2-8.4, p=0.02); ever had other STIs (OR=1.6, 95% CI 1.1-2.3, p=0.009); no formal maternal education (OR=0.6, 95% CI 0.4-0.9, p=0.021) and having one lifetime sexual partner (OR=0.4, 95% CI 0.3-0.5, p<0.00001) were significantly associated with HIV infection in the study population. Appropriate interventions must be directed at young people and should include STI control and abstinence education. Blood safety must be ensured as well as a general improvement in the level of formal and health education in this community.     

Effect of gonadotropin-releasing hormone agonist treatment in boys with central precocious puberty: final height results

OBJECTIVE: The small number of boys present in most studies on final height (FH) after gonadotropin-releasing hormone agonist (GnRHa) treatment for central precocious puberty (CPP) offers difficulties in the evaluation of the effects of treatment on FH in males. METHOD: We therefore combined FH data from The Netherlands, Italy and France to study the effect of GnRHa treatment in a large group of 26 boys with CPP. RESULTS: The mean chronological age at the start of treatment was 7.6 +/- 2.0 (SD) years, bone age (BA) was 11.0 +/- 2.1 years. All boys were treated with depot formulations of the GnRHa triptorelin with established gonadal suppression for a mean treatment period of 4.7 +/- 2.1 years. FH was 172.9 +/- 6.6 cm. FH standard deviation score (SDS) was -0.66 +/- 1.22, not significantly different from the target height SDS of -0.23 +/- 0.75. FH-SDS was significantly lower in the subgroup of 12 patients with organic CPP compared to patients with idiopathic CPP (-1.34 +/- 1.06 vs. -0.08 +/- 1.06, respectively; p = 0.01), but no difference in height gain was observed. The mean estimated height gain, defined as the difference between predicted and actual adult height was 6.2 +/- 8.7 cm using the average tables of Bayley and Pinneau, and 0.3 +/- 8.6 cm using the BA advance adjusted tables. Regional differences in height gain were observed between the different countries, reflecting different local practices. CONCLUSION: We conclude that GnRHa treatment in boys results in a FH close to target height.     

Acne in schoolchildren: no longer a concern for dermatologists.

OBJECTIVE--To determine the prevalence and severity of acne among schoolchildren in Glasgow. DESIGN--Secondary schools in Glasgow were divided by postcode into five socioeconomic cluster groups. Different numbers of schools were selected at random from the five groups to ensure proportional representation. One class from each registration year of the chosen schools was selected at random and the whole class recruited into the study. SETTING--15 Secondary schools in Glasgow. SUBJECTS--2014 Randomly selected schoolchildren aged 12-17 (5% of total secondary school roll). INTERVENTIONS--None. END POINT--Assessment of facial acne by two independent examiners by a recognised acne scoring system. MEASUREMENTS AND MAIN RESULTS--The prevalence of acne in boys increased from 40% (75/189) at age 12 to 95% (108/114) at age 16, and in girls it increased from 61% (114/187) at age 12 to 83% (136/164) at age 16. On a scale of 0 to 10 only 18 boys (1.8%) and three girls (0.3%) had grades of acne of 1.0 or greater; most of the pupils had grade 0.05-0.375 (minimal) acne. Nine per cent of boys (88/973) and 14% of girls (145/1041) had visited their general practitioner specifically for advice on and treatment for acne; only five pupils (0.3%) had been referred to a dermatologist. CONCLUSIONS--Both the prevalence and severity of acne have decreased over the past 20 years. This has probably been due to improvement of treatment for acne by primary care doctors and the greater availability and use of over the counter preparations for acne.     

Diazepam binding inhibitor (DBI) reduces testosterone and estradiol levels in vivo

Diazepam binding inhibitor (DBI) is a putative endogenous ligand capable of binding to the central type benzodiazepine (BZD) receptor located on the GABAA receptor and the peripheral type BZD receptor on the mitochondrial outer membrane. We examined the effects of an intracerebroventricular injection of DBI on the serum levels of the gonadal hormones, testosterone and estradiol, respectively, in male and female mice. DBI (0.3-10 nmol/mouse, i.c.v.) significantly reduced the levels of both gonadal hormones in a dose-dependent manner. The decrease in the gonadal hormone levels became evident at 1 hr and lasted for at least 4 hrs after the DBI injection. The effects of DBI (3 nmol/mouse, i.c.v.) in male and female mice were completely attenuated by the coadministration of flumazenil (66 nmol/mouse), a selective antagonist for the central type BZD receptor. These results suggest that DBI acts as an endogenous modulator to regulate the levels of gonadal hormones in vivo, and that the DBI-induced decrease in gonadal hormone levels is mediated by down regulation of the GABAergic system, implicated in gonadotropin-releasing systems and/or the hypothalamic-pituitary-gonadal axis.     

Comparable testosterone responses are produced by constant infusion of LH or GnRH in normal men

Luteinizing hormone (LH) was infused continuously at a rate of 1.3 IU/min to 4 normal adult men. A 4 to 5-fold increase in serum LH was noted by 8 hours. Serum FSH declined steadily throughout the infusion period in the face of rising concentrations of gonadal steroids. Basal plasma testosterone of 4.7 +/- 0.4 ng/ml rose progressively to a peak of 11.1 +/- 0.9 ng/ml at hour 56 (p less than 0.005). A similar pattern was demonstrated by plasma androstenedione. Plasma 17 alpha-hydroxyprogesterone rose from a basal concentration of 0.81 +/- 0.14 ng/ml to a peak concentration of 2.6 +/- 0.3 ng/ml at hour 36 of the infusion and subsequently declined. A similar course was followed by serum estradiol-17 beta, which achieved a maximal concentration of 70.0 +/- 10.4 pg/ml at hour 36. Results are compared to those obtained with continuous infusion of GnRH in normal adult men. Testosterone responses were similar, whereas elevations in 17 alpha-hydroxyprogesterone and estradiol were higher following GnRH infusion. This difference may be consequent upon a direct gonadal effect of GnRH, or may be secondary to local regulation of testicular steroidogenesis by estradiol-17 beta.