The risk of mental disorders in patients with disorders/differences of sex differentiation/development (DSD) and Y chromosome

Introduction: Patients with disorders/differences of sex differentiation/development (DSD) are exposed to physical and mental suffering. The aim of the study was to assess the following: the mental health status and the risk of mental problems in adult DSD patients, their dependence on therapeutic procedures, and to identify groups of disorders that require particular psychological support. Material and methods: The study involved 59 patients with DSD (gonadal dysgenesis — GD, androgen insensitivity syndrome — AIS, 5-alpha reductase deficiency, ovotestis), and with the Y chromosome in the karyotype, aged 16–65 years. All completed the General Health Questionnaire (GHQ-28) for the assessment of their mental health status. Raw results were converted into sten scores using norms for the Polish adult population to assess the risk of mental problems. Results: A high risk of mental problems was identified in 24% of individuals (26% men, 21% women). Women, when compared with men, displayed a significantly higher mean level of anxiety and insomnia (7.3 vs. 4.6 scores) and somatic symptoms (7.4 vs. 5.5), and worse general mental health status (25.6 vs. 18.8). The most disturbing symptoms were observed among patients with complete and partial AIS, and complete GD (general mental health status: 39.5, 24.3, and 24.2, respectively), women lacking a vagina (27.2), and without an enlarged clitoris (27.5). Patients after genital surgery had significantly fewer somatic symptoms (5.4 vs. 7.8; p < 0.05) and better general mental health status in comparison to those without surgery (20.1 vs. 24.9; p < 0.05). No significant differences were observed between patients using hormone replacement therapy and those who were not. Conclusions: The individuals with DSD and Y chromosome in the karyotype have increased risk of developing mental problems in comparison to the general Polish population. The risk factors seem to be as follows: female gender, the lack of a vagina, the lack of virilisation (no enlarged clitoris), and no genital operations performed. In some cases, sex hormone replacement therapy may be also the risk of mental problems. Particularly vulnerable groups are CAIS, PAIS, and CGD. The psychological support and an individual approach to particular needs of these patients is necessary.

Administration of testosterone inhibits initiation of seminal tubule growth and decreases Sertoli cell number in the earliest period of rat's postnatal development.

Sertoli cell (SC) number determines testes size and their capacity to produce spermatozoa. In the rat SC proliferate until 15th postnatal day (PND). Their proliferation is stimulated by FSH and inhibited by estradiol, but the role for androgens is uncertain. In this study we analyzed the effects of testosterone administration on testes growth and SC number in relation to timing of the treatment. Male rats were injected with 2.5 mg of testosterone propionate (TP) from birth until 5th PND and autopsied either on 6th PND [TP1-5(6)] or on 16th PND [TP1-5(16)] (transient administration). Other rats received TP from birth until 15th PND [TP1-15] or between 5th and 15th PND [TP5-15] continuously and were autopsied on day 16th. Control groups (C) received vehicle. In the Cs serum level of estradiol was 20-fold higher (

Daily levels of sex hormones in 15 subfertile women formulate a menstrual cycle profile predominant with progesterone secretion

Introduction: Changes in sex hormone secretions during the menstrual cycle may affect fertility. It has been shown that a prematurely raised progesterone (P4) level after therapeutic injection of human chorionic gonadotropin caused changes in endometrial gene expression and lowered the pregnancy rate. The aim of the present study was to investigate the complete menstrual patterns of P4 together with its derivatives testosterone (T) and oestradiol (E2) in subfertile women during their natural cycles. Material and methods: Daily serum levels of P4 (ng/mL), T (ng/mL), E2 (pg/mL), and sex hormone binding protein (SHBG, nmol/L) were measured throughout a single 23–28-day menstrual cycle in 15 subfertile women aged 28–40 years with patent oviducts and normospermic partners. Knowing SHBG levels, the free androgen (FAI) and free oestrogen (FEI) indexes were calculated for each cycle day in each patient. Results: Baseline (cycle day one) levels of luteinising hormone (LH), thyroid stimulating hormone (TSH), P4, and T were comparable with reference intervals for a normal cycle, whereas follicle stimulating hormone (FSH), E2, and SHBG exceeded those. During cycles, the levels of P4 correlated positively with E2 levels (r = 0.38, p < 0.05, n = 392) an  negatively with T (r = –0.13, p < 0.05, n = 391). T correlated negatively with E2 (r = –0.19, p < 0.05, n = 391). Menstrual cycle phases were hidden. The curve of the mean/median daily levels of P4 rose prematurely, was parallel with the E2 rise, and culminated closely, but with more than 4 times greater amplitude of P4 (2571% of baseline levels in day 16) than of E2 (580% in day 14). In turn, the curve of T declined in a U-shaped manner with a nadir (–27%) on day 16. Averaged daily levels of FEI, but not FAI, varied significantly between 23 and 26 days long and the 27–28-day cycles. Conclusions: 1. Throughout the entire menstrual cycle length in subfertile women, P4 secretion predominates quantitatively over secretions of the remaining sex hormones when menstrual cycle phases are hidden. 2. The rise of E2 secretion is in parallel with the P4 rise, but with 4 times lower amplitude of E2. 3. T secretion declines and is inversely related to both P4 and E2 secretions. 4. Changes in E2 bioavailability are related to menstrual cycle length.

Xenoestrogens diethylstilbestrol and zearalenone negatively influence pubertal rat's testis.

The aim of this study was to assess the impact of xenoestrogens: diethylstilbestrol (DES) and zearalenone (ZEA) on rat's pubertal testis and to compare it with the effect of natural estrogen - 17beta-estradiol (E). Male Wistar rats were daily, subcutaneously injected at 5th-15th postnatal days (p.d.) with E (1.25 or 12.5 mug) or DES (1.25 or 12.5 mug) or ZEA (4 or 40 mug) or vehicle. At 16th p.d. testes were dissected, weighted, and paraffin embedded. Following parameters were assessed: diameter and length of seminiferous tubule, numbers of spermatogonia A+intermediate+B (A/In/B), preleptotene spermatocytes (PL), leptotene+zygotene+pachytene spermatocytes (L/Z/PA) and Sertoli cells per testis. Testes weight, seminiferous tubule diameter and length were decreased by both doses of E, DES and ZEA. DES effect was the strongest, but its influence on testis weight and seminiferous tubule length, on the contrary to E and ZEA, was not dose-dependent. Similarly, DES in both doses had the most severe negative impact on the number of germ and Sertoli cells. The negative influence of E on germ cells was less pronounced. The negative effect of ZEA was seen only after administration of the higher dose on spermatogonia number, while DES and E decreased A/In/B number more evidently. Sertoli cell number were decreased after both doses of E. ZEA40 decreased Sertoli cell number while ZEA4 had no effect. Conclusion: exposure of prepubertal male rat to DES has the strongest detrimental effect on the developing testis in comparison to E and ZEA. Both, E and DES, decreased number of germ and Sertoli cells, diminished seminiferous tubule diameter, length and testis weight. ZEA had much more weaker effect than the potent estrogens

Zależność pomiędzy funkcją seksualną a wskaźnikiem masy ciała i stężeniem hormonów steroidowych u młodych mężczyzn

Introduction: In older men, sexual disorders may be the result of a decrease in testosterone and an increase in sex hormone binding globulin (SHBG) serum levels. Although obesity may enhance the decline of testosterone, it is also the cause of metabolic disorders, which are additional risk factors of erectile dysfunction. The purpose of this study was to investigate whether elevated body weight is associated with decreased serum testosterone concentrations and reduced sexual function in young men.Material and methods: Data on general health, medication, depressive symptomatology and sexual life was obtained from 136 men aged 20–49 years. Blood levels of LH, total testosterone (TT), dehydroepiandrosterone sulfate (DHEA-S), oestradiol, SHBG, total cholesterol, LDL- and HDL-cholesterol, and triglycerides were determined. Body mass index (BMI), waist to hip ratio (WHR) and free testosterone index (FTI) were calculated.Results: A significantly reduced occurrence of sexual fantasies, morning erections and erectile function scores was observed in the oldest group compared to the youngest men with normal BMI, although orgasmic function was unchanged. A significant decrease in TT serum levels was observed in obese 30-year-olds compared to men with normal BMI, while in obese 40-year-olds decreased LH and SHBG levelswere also found. No differences in the levels of lipids and sexual achievements were found among men with different BMI. However, erectile function and morning erections significantly negatively correlated with age, BMI and WHR, and positively with FTI, but not with other studied hormones and lipids.Conclusions: In young men, obesity can lead to a deterioration of erectile function as a result of lower testosterone levels as the only reason.Wstęp: U starszych mężczyzn zaburzenia seksualne mogą być następstwem zmniejszania się stężenia testosteronu i wzrostu stężeniaglobuliny wiążącej steroidy płciowe (SHBG) we krwi. Otyłość może nasilać obniżanie stężenia testosteronu, ale jest także przyczyną zaburzeńmetabolicznych, które stanowią dodatkowe ryzyko pojawienia się zaburzeń erekcji. Celem pracy było zbadanie, czy nadmiernamasa ciała jest związana z obniżonym stężeniem testosteronu i pogorszeniem funkcji seksualnych już u młodych mężczyzn.Materiał i metody: Dane na temat stanu zdrowia, stosowanych leków, objawów depresji i życia seksualnego uzyskano od 136 mężczyzn w wieku 20–49 lat. We krwi oznaczono stężenia LH, testosteronu całkowitego (TT), siarczanu dehydroepiandrosteronu (DHEA-S), estradiolu, SHBG, cholesterolu całkowitego, cholesterolu LDL i HDL oraz triglicerydów. Wyliczono wskaźniki: masy ciała (BMI), talia/biodra (WHR) i wolnego testosteronu (FTI).Wyniki: Znamienne zmniejszenie częstości fantazji seksualnych i porannych erekcji oraz pogorszenie jakości erekcji, ale nie zdolności do osiągania orgazmu, obserwowano w najstarszej grupie badanych w porównaniu z grupą najmłodszych mężczyzn z prawidłowym BMI. Znamienne zmniejszenie stężenia TT stwierdzono u otyłych 30-latków w porównaniu z mężczyznami z prawidłowym BMI, a u 40-latków dodatkowo stwierdzono zmniejszenie stężenia LH i SHBG. Nie stwierdzono znamiennych różnic w stężeniu lipidów, a także w jakości reakcji seksualnych u mężczyzn z różnym BMI. Jednakże, jakość erekcji oraz częstość występowania porannych erekcji znamiennie negatywnie korelowały z wiekiem, BMI i WHR, a pozytywnie z FTI, ale nie z innymi badanymi hormonami i lipidami.Wnioski: U młodych mężczyzn otyłość może prowadzić do pogorszenia erekcji na skutek obniżenia stężenia testosteronu jako jedynej przyczyny

Di(n-butyl) phthalate has no effect on the rat prepubertal testis despite its estrogenic activity in vitro

The aim of this study was to assess the impact of di(n-butyl) phthalate (DBP) on the rat’s prepubertal testis. Male Wistar rats were given daily subcutaneous injections with DBP (20 or 200 μg) or a vehicle from the 5th to the 15th postnatal day (pd). On the 16th pd, the rats were euthanized, and the testes were dissected, weighed, and paraffin embedded. The blood was collected to determine the serum levels of testosterone (T), estradiol (E) and FSH. The following parameters were assessed in the testis sections: diameter and length of seminiferous tubules (st), numbers of spermatogonia A + intermediate + B (A/In/B), preleptotene spermatocytes (PL), leptotene + zygotene + pachytene spermatocytes (L/Z/PA) and Sertoli cells per testis, percentage of st containing gonocytes or pachytene spermatocytes or lumen. An estrogenicity in vitro test was performed by means of a transgenic yeast strain expressing human estrogen receptor alpha. At both doses, DBP had no influence on testis and seminal vesicle weight, st diameter and length, number of germ and Sertoli cells per testis, percentage of st containing gonocytes or pachytene spermatocytes or lumen. DBP did not change E, T or FSH serum levels. The in vitro yeast screen showed that DBP was a weak estrogenic compound, approximately six to seven orders of magnitude less potent than 17β-estradiol. In conclusion, exposure of a rat to DBP in doses 100 or 1,000-fold higher than a Tolerable Daily Intake for humans had no effect on its testicular development. (Folia Histochemica et Cytobiologica 2011; Vol. 49, No. 4, pp. 685–689

Features of impaired seminiferous tubule differentiation are associated with germ cell neoplasia in adult men surgically treated in childhood because of cryptorchidism.

Seminiferous tubule differentiation was related to the occurrence of germ cell neoplasia in 38 men, aged 17-47, treated surgically in childhood for cryptorchidism. Tissues from 46 testes obtained from biopsies taken as a neoplastic preventive procedure or whole testes removed because of GCT were evaluated quantitatively. Paraffin sections were treated with antibodies against placental like alkaline phosphatase (PLAP), a marker of germ cell neoplasia, and cytokeratin 18 (CK-18), a marker of immature Sertoli cells. Quality of spermatogenesis and number Leydig cells were assessed with a score count. Seminiferous tubules diameter, thickness of basal membrane and size of intertubular spaces were measured with image analysis software. In 17.4% of testes spermatogenesis was normal (9.9 points) (N) and neoplasia was not found there. In the other 38 specimens (83%) spermatogenesis was abnormal (A). When spermatogenesis was arrested or when germ cells were absent (3.7+/-1.8 points), neoplastic lesions were found in 13.1% of the specimens. In A group 5.1+/-7.1% of tubules contained immature Sertoli cells, while in N they were not found. Tubular diameter was significantly lower in A (161.5+/-31.8 microm) than in N (184.6+/-24.3 microm) and the percentage of seminiferous tubules with the thickening of tubular basal membrane was also greater in A. Intertubular spaces were significantly larger in A (49.9+/-18.6%) in comparison to N group (32.6+/-12.5%). Mean number of Leydig cells was similar in both groups. To conclude, in most of the formerly cryptorchid testes, despite surgical treatment, impaired seminiferous tubules differentiation is predominant. Germ cell neoplasia is present in testes with retarded seminiferous tubules differentiation. Retardation of seminiferous tubule differentiation consists of inhibited spermatogenesis, presence of tubules with immature Sertoli cells, decreased tubular diameter, increased thickness of basal membrane and enlarged intertubular spaces. Examination of testicular biopsy with respect to the state of seminiferous tubule differentiation may be helpful to predict the appearance of germ cell neoplasia in adult men with cryptorchidism in anamnesis. Orchiopexy of cryptorchid testes may not prevent the occurrence of features of testicular dysgenesis and the associated germ cell neoplasia

Wolne i biodostępne frakcje steroidów płciowych mogą wpływać na kości u młodych mężczyzn w zależności od wieku i stężenia estradiolu

Introduction: Longitudinal bone growth ceases by the end of puberty, and it is thought to be a result, in both sexes, of increased pubertal oestrogen serum concentrations. Since peak bone mass is achieved by the third decade of life or later, the aim of this study was to relate sex steroid hormones and sex hormone binding globulin (SHBG) levels to bone quality in men during their third and fourth decades of life.Material and methods: Eighty men, healthy volunteers aged between 18 and 39 years, were subjected to an interviewer-administered questionnaire, body mass index (BMI) measurement, blood sample and calcaneal quantitative ultrasound (QUS) (Hologic-SAHARA). Blood was assessed for testosterone (T), oestradiol (E2), dehydroepiandrosterone sulfate (DHEAS), SHBG, luteinising hormone (LH) and follicle stimulating hormone (FSH). Free and bioavailable T and E2 levels were calculated knowing SHBG and albumin levels.Results: While T, E2, DHEAS, LH and FSH levels were not related, free and bioavailable fractions of T and E2 were positively associated with QUS readings. SHBG level was associated negatively. After dichotomisation for age, the associations remained significant only for younger subjects (18–30 years, n = 47). After adjustment for other co-variants, only SHBG in younger subjects retained its negative association with QUS. Older subjects (31–39 years, n = 33) revealed higher BMI and lower serum concentrations of total (–17 %), free (–18.5%) and bioavailable (–22.5%) levels of E2 than younger subjects.Conclusion: Free and bioavailable fractions of sex steroids may influence bones in young men, depending on age and E2 level. (Endokrynol Pol 2014; 65 (5): 357–364)Wstęp: Wzrost kości na długość ustaje wraz z końcem dojrzewania płciowego i wykazano, że u obu płci jest to wynik wzrostu stężenia estrogenów we krwi. Skoro przyjęto, że szczytowa masa kostna jest osiągana dopiero w trzeciej dekadzie życia lub po trzydziestce, badano związki pomiędzy stężeniami steroidów płciowych i białka wiążącego steroidy płciowe (SHBG) a jakością kości u mężczyzn w trzeciej i czwartej dekadzie życia.Materiał i metody: Osiemdziesięciu mężczyzn, zdrowych ochotników w wieku 18–39 lat wypełniło kwestionariusz z wywiadem, zmierzono u nich wskaźnik masy ciała (BMI) i wykonano ilościową analizę ultrasonograficzną kości piętowej (QUS) (Hologic-SAHARA). We krwi oznaczono stężenia testosteronu (T), estradiolu (E2), siarczanu dehydroepiandrosteronu (DHEAS), SHBG, hormonu luteinizującego (LH) i hormonu folikulotropowego (FSH). Znając stężenia SHBG i albumin, wyliczano stężenia wolnego i biodostępnego T i E2.Wyniki: Podczas gdy stężenia T, E2, DHEAS, LH i FSH nie wykazywały powiązań, stężenia wolnych i biodostępnych frakcji T i E2 były dodatnio związane z parametrami QUS. Stężenie SHBG wykazywało związek ujemny. Relacje te zależały od wieku. Mianowicie, po podziale na dwie grupy wiekowe, relacje pozostały znamienne tylko wśród młodszych mężczyzn (18–30 lat, n = 47). Analiza wieloczynnikowa wykazała, że tylko stężenie SHBG u młodszych mężczyzn zachowało znamiennie ujemny związek ze stanem kości. Starsi (31–39 lat, n = 33) wykazali wyższy BMI, a niższe stężenie całkowitego (–17%), wolnego (–18,5%) i biodostępnego (–22,55%) E2 w porównaniu z młodszymi badanymi.Wnioski: Wolne i biodostępne frakcje steroidów płciowych mogą wpływać na kości u młodych mężczyzn, w zależności od wieku i stężenia E2. (Endokrynol Pol 2014; 65 (5): 357–364

Physiological significance of estrogens in men - breakthrough in endocrinology

Estradiol (E2) jest tradycyjnie uznanym żeńskim hormonem płciowym. Przez 40 lat wierzono, że u mężczyzn E2 nie wywiera żadnego wpływu lub wywołuje uszkodzenie czynności gonady. Głównym źródłem E2 u mężczyzn jest tkanka tłuszczowa i mózg. E2 jest również wytwarzany w nadnerczach, wątrobie, gruczołach sutkowych i włosach oraz w gonadzie męskiej. Dzienne wytwarzanie i stężenie E2 we krwi u mężczyzn są wyższe niż u kobiet w okresie pomenopauzalnym. W końcu lat 80. wykazaliśmy po raz pierwszy, że w okresie dojrzewania płciowego E2 jest istotnym sygnałem hormonalnym dla zapoczątkowania spermatogenezy. Tradycyjny pogląd o braku lub hamującej roli E2 u płci męskiej został ostatecznie obalony dzięki odkryciu receptorów estrogenowych u samców zwierząt. W latach 90. wytworzono też samce myszy transgenicznych pozbawione receptora estrogenowego (ER), a także genu kodującego enzym aromatazę, umożliwiającego konwersję testosteronu do E2. Obserwacje dorosłych mężczyzn z wrodzonymi mutacjami tych genów, znacznie poszerzyły naszą wiedzę na temat roli E2 u mężczyzn przy tworzeniu zrębu kości, hamowaniu ich wzrostu, metabolizmie lipidów i dojrzewaniu płciowym, efektom przypisywanym dotychczas działaniu testosteronu. Nowe dane wskazują także na ważną rolę estrogenów i ER w czynności układu sercowo-naczyniowego i w przeciwdziałaniu chorobie wieńcowej u mężczyzn.Estradiol (E2) is traditionally recognised as the female sex hormone. It has been believed for 40 years, that E2 didn’t exert any influence or caused impairment of the gonadal function in men. The main source of E2 in men is adipose tissue and the brain. E2 is also produced in adrenals, liver, mammary glands, hair and in male gonad. Daily production and the level of E2 in the blood in men are higher than those in postmenopausal women. At the end of the 80-ties we were first reporting that during sexual maturation E2 can be the important hormonal signal for the initiation of spermatogenesis. The traditional view about unimportant or inhibitory role of E2 in male physiology was finally refuted thanks to discovering estrogen receptors in males. In the 90-ties, transgenic mice with the lack of estrogen receptor (ER) or gene encoding enzyme aromatase, that enable the conversion of testosterone into E2, were also produced. Observations of men with inherited mutations of these genes, considerably extended our knowledge about E2 in men in stroma bones formation, inhibition of their growing, lipids metabolism and sexual maturation, the effects that were attributed to testosterone action until today. New data also points at important role of estrogens and ER in the function of the cardio-vascular system and in counteracting coronary disease in men