Gender-affirming hormone treatment: friend or foe? Long-term follow-up of 755 transgender people.

PURPOSE: Gender-affirming hormone treatment (GAHT) is one of the main demands of transgender and gender diverse (TGD) people, who are usually categorised as transgender assigned-male-at birth (AMAB) and assigned-female-at birth (AFAB). The aim of the study is to investigate the long-term therapeutic management of GAHT, considering hormonal targets, treatment adjustments and GAHT safety. METHODS: A retrospective, longitudinal, observational, multicentre clinical study was carried out. Transgender people, both AMAB and AFAB, were recruited from two Endocrinology Units in Italy (Turin and Modena) between 2005 and 2022. Each subject was managed with specific and personalized follow-up depending on the clinical practice of the Centre. All clinical data routinely collected were extracted, including anthropometric and biochemical parameters, lifestyle habits, GAHT regime, and cardiovascular events. RESULTS: Three-hundred and two transgender AFAB and 453 transgender AMAB were included. Similar follow-up duration (p = 0.974) and visits' number (p = 0.384) were detected between groups. The transgender AFAB group reached therapeutic goals in less time (p = 0.002), fewer visits (p = 0.006) and fewer adjustments of GAHT scheme (p = 0.024). Accordingly, transgender AFAB showed a higher adherence to medical prescriptions compared to transgender AMAB people (p < 0.001). No significantly increased rate of cardiovascular events was detected in both groups. CONCLUSION: Our real-world clinical study shows that transgender AFAB achieve hormone target earlier and more frequently in comparison to transgender AMAB individuals. Therefore, transgender AMAB people may require more frequent check-ups in order to tailor feminizing GAHT and increase therapeutic adherence.

POR polymorphisms are associated with 21 hydroxylase deficiency.

PURPOSE: Genotype-phenotype correlation in congenital 21 hydroxylase deficiency is strong but by no means absolute. Indeed, clinical and hormonal features may vary among patients carrying similar CYP21A2 mutations, suggesting that modifier genes may contribute to the phenotype. Aim of the present study was to evaluate whether polymorphisms in the p450  oxidoreductase (POR) gene may affect clinical features in patients with 21 hydroxylase deficiency METHODS: Sequencing of the POR gene was performed in 96 patients with 21 hydroxylase deficiency (49 classic, 47 non-classic) and 43 control subjects. RESULTS: Prevalence of POR polymorphisms in patients with 21 hydroxylase was comparable to controls and known databases. The rs2228104 polymorphism was more frequently associated with non-classic vs classic 21 hydroxylase deficiency (allelic risk 7.09; 95% C.I. 1.4-29.5, p < 0.05). Classic 21 hydroxylase-deficient carriers of the minor allele in the rs2286822/rs2286823 haplotype presented more frequently the salt-wasting form (allelic risk 1.375; 95% C.I. 1.138-1.137), more severe Prader stage at birth (allelic risk 3.85; 95% C.I. 3.78-3.92), higher ACTH levels, and younger age at diagnosis. CONCLUSIONS: Polymorphisms in the POR gene are associated with clinical features of 21 hydroxylase deficiency both as regards predisposition to classic vs non-classic forms and severity of classic adrenal hyperplasia.

Quality of life and hormones after sex reassignment surgery.

BACKGROUND: Transpeople often look for sex reassignment surgery (SRS) to improve their quality of life (QoL). The hormonal therapy has many positive effects before and after SRS. There are no studies about correlation between hormonal status and QoL after SRS. AIM: To gather information on QoL, quality of sexual life and body image in transpeople at least 2 years after SRS,to compare these results with a control group and to evaluate the relations between the chosen items and hormonal status. SUBJECTS AND METHODS: Data from 60 transsexuals and from 60 healthy matched controls were collected. Testosterone,estradiol, LH and World Health Organization Quality of Life (WHOQOL-100) self-reported questionnaire were evaluated. Student's t test was applied to compare transsexuals and controls. Multiple regression model was applied to evaluate WHOQOL's chosen items and LH. RESULTS: The QoL and the quality of body image scores intranspeople were not statistically different from the matched control groups' ones. In the sexual life subscale,transwomen's scores were similar to biological women's ones, whereas transmen's scores were statistically lower than biological men's ones (P = 0.003). The quality of sexual life scored statistically lower in transmen than intranswomen (P = 0.048). A significant inverse relationship between LH and body image and between LH and quality of sexual life was found. CONCLUSIONS: This study highlights general satisfaction after SRS. In particular, transpeople's QoL turns out to be similar to Italian matched controls. LH resulted inversely correlated to body image and sexual life scores.

Medical treatment in gender dysphoric adolescents endorsed by SIAMS-SIE-SIEDP-ONIG.

PURPOSE: Despite international guidelines being available, not all gender clinics are able to face gender dysphoric (GD) youth population needs specifically. This is particularly true in Italy. Centers offering specialized support are relatively few and a commonly accepted Italian approach to GD youth has still not been defined. The aim of the present Position Statement is to develop and adhere to Italian guidelines for treatment of GD adolescents, in line with the "Dutch Approach", the Endocrine Society (ES), and the World Professional Association for Transgender Health (WPATH) guidelines. METHODS: An in-depth brainstorming on the application of International guidelines in the Italian context was performed by several dedicated professionals. RESULTS: A staged approach, combining psychological support as well as medical intervention is suggested. In the first phase, individuals requesting medical help will undergo a psycho-diagnostic procedure to assess GD; for eligible adolescents, pubertal suppression should be made available (extended diagnostic phase). Finally, from the age of 16 years, cross-sex hormonal therapy can be added, and from the age of 18 years, surgical sex reassignment can eventually be performed. CONCLUSIONS: The current inadequacy of Italian services offering specialized support for GD youth may lead to negative consequences. Omitting or delaying treatment is not a neutral option. In fact, some GD adolescents may develop psychiatric problems, suicidality, and social marginalization. With access to specialized GD services, emotional problems, as well as self-harming behavior, may decrease and general functioning may significantly improve. In particular, puberty suppression seems to be beneficial for GD adolescents by relieving their acute suffering and distress and thus improving their quality of life.

Genotype, phenotype and hormonal levels correlation in non-classical congenital adrenal hyperplasia.

Non-classical congenital adrenal hyperplasia (NCAH) is a morbid condition sustained by the reduced function of one of the enzymes involved in the adrenal steroid biosynthesis pathway, mainly the 21-hydroxylase. Different degrees of enzyme activity impairment determine different clinical pictures, with childhood or post-pubertal onset. The aim of this study was to evaluate the relationship between genotype, phenotype, and adrenal hormonal levels in a group of 66 patients affected by NCAH attending outpatient pediatric or endocrinological Clinics. Our findings show that age at pubarche/menarche was significantly younger, height SD score) and Δ bone age-chronological age were significantly higher in patients with a more severe enzyme activity impairment, while cutaneous androgenization and menstrual irregularities in post-pubertal girls were not related to the grading of genotype.

Correlation between genotype and hormonal levels in heterozygous mutation carriers and non-carriers of 21-hydroxylase deficiency.

Congenital adrenal hyperplasia, both in its classic (CCAH) and non-classic form (NCAH), is a morbid condition sustained by the absent or reduced function of one of the enzymes involved in cortisol biosynthesis - mainly 21 hydroxylase - associated with different levels of clinical androgenization. In a wide group of relatives of patients affected by CCAH and NCAH (no.=222) and healthy volunteers (no.=30), a clinical, hormonal and genetic evaluation was performed in order to differentiate between the condition of heterozygous mutation carrier and non-carrier of any among 21-hydroxylase gene (CYP21) mutations. This study shows that clinical presentation and basal 17α-hydroxyprogesterone (17α-OHP) are not able to differentiate between heterozygous carriers and non-carriers, whereas 17α-OHP value after ACTH bolus is significantly different between heterozygous carriers and non-carriers: p<0.001 with a cut-off value of 3 ng/ml (90% sensitivity and 74,3% specificity). Moreover, our data indicate that 17α-OHP response to ACTH may be a useful tool to select subjects for genetic analysis.

Male sexual disturbances in liver diseases: what do we know?

The alterations of sexual function known as the erectile dysfunction are quite frequent among patients affected by liver diseases and they tend to increase in advanced liver failure. This process is directly linked to cirrhosis or its treatments, such as liver transplantation, or to certain drugs (e.g. beta-blockers). Independent of cirrhosis, other factors may cause sexual problems in these patients. Alcohol itself seems to worsen sexual function in the absence of cirrhosis. Viral hepatitis has an uncertain influence on male gonadic function and even antiviral therapy itself can worsen some seminal and hormonal parameters, although it is reversible. Quality of life may be greatly decreased in cases of cirrhosis where these alterations are present, so it is important to value and care for them, if possible. This review investigates the major male sexual disturbances in liver diseases of various origins.

Exogenous platelet-activating factor improves the motility of human spermatozoa evaluated with C.A.S.A.: optimal concentration and incubation time.

The objective of this study is to determine the optimal conditions for human semen incubation treated with exogenous platelet activating factor (ePAF) for intra-uterine insemination (IUI). This prospective study was carried out on 32 infertile men and each semen sample was processed with the ISolate Sperm Separation Medium, washed with sperm washing medium (SWM) and resuspended either in SWM alone (control samples), or with ePAF 0.1, 0.5, and 1.0 µM. Each concentration was subsequently incubated and evaluated at 5, 15, 30, and 60 min. The motility parameters were evaluated by the computer-aided sperm analysis (C.A.S.A.) system. Curvilinear velocity, straight line velocity, average path velocity, rapid and progressive motility significantly increased compared to control samples at an ePAF concentration of 0.1 µM (with at least 15 min of incubation). The best results were obtained with ePAF concentrations of: 0.1 µM (60 min of incubation) and 0.5 µM (30-60 min of incubation). In conclusion, results are enhanced when ePAF is added to standard semen preparation for IUI. An ePAF concentration of 0.1 µM, with an incubation time of 15 min, can be used for semen samples with normal motility. Whilst, for semen samples with poor motility, the ePAF concentration is best increased to 0.5 µM and/or the incubation time prolonged to 60 min.

Prolonged treatment with N-acetylcysteine and L-arginine restores gonadal function in patients with polycystic ovary syndrome.

Nitric oxide (NO) plays a wide spectrum of biological actions including a positive role in oocyte maturation and ovulation. Free radicals levels have been shown elevated in polycystic ovary syndrome (PCOS) and therefore would be responsible for quenching NO that, in turn, would play a role in determining oligo- or amenorrhea connoting PCOS. Eight patients with PCOS displaying oligo-amenorrhea from at least 1 yr underwent a combined treatment with N-acetylcysteine (NAC) (1200 mg/die) plus L-arginine (ARG) (1600 mg/die) for 6 months. Menstrual function, glucose and insulin levels, and, in turn, homeostasis model assessment (HOMA) index were monitored. Menstrual function was at some extent restored as indicated by the number of uterine bleedings under treatment (3.00, 0.18-5.83 vs 0.00, 0.00-0.83; p<0.02). Also, a well-defined biphasic pattern in the basal body temperature suggested ovulatory cycles. The HOMA index decreased under treatment (2.12, 1.46-4.42 vs 3.48, 1.62-5.95; p<0.05). In conclusion, this preliminary, open study suggests that prolonged treatment with NAC+ARG might restore gonadal function in PCOS. This effect seems associated to an improvement in insulin sensitivity.

Multiple endocrine neoplasia (MEN IIB) with Cushing's syndrome due to medullary thyroid carcinoma producing corticotropin-releasing hormone.

We describe a case of Cushing's syndrome caused by a medullary thyroid carcinoma (MCT) secreting corticotropin-releasing-hormone (CRH) in a young woman presenting mucosal neuromas located on the top of the tongue and eyelid areas. Laboratory studies showed, basally and after dexamethasone suppression test, serum cortisol and plasma pituitary corticotrophin (ACTH) levels agreed with an ectopic Cushing's syndrome. Immunohistochemical studies of the MCT tissue revealed a production of CRH and scattered cells containing vasopressin but not ACTH peptides. This is the first demonstrated case of a CRH-secreting tumor in multiple endocrine neoplasia (MEN IIB) syndrome.

Oral and topical spironolactone therapies in skin androgenization.

The most important clinical studies using spironolactone as an antiandrogen drug either per os or topically are referred. Menstrual disturbances very often occur during SP treatments thus limiting its systemic use. As far as the topical use is concerned SP seems to be highly effective with absence of systemic effects. Local mild side effects were present in a small number of patients.

Gonadotroph cell pituitary adenomas in males.

BACKGROUND: Considered exceptional in the past, gonadotroph cell pituitary adenomas account for 3.5-6.4% of total surgically excised pituitary adenomas when examined with immunospecific staining. The aim of this study was to describe the clinical, hormonal, radiological and immunohistochemical features, the management and the follow-up of our patients with gonadotroph adenoma. METHODS: In this retrospective study we describe 14 male subjects aged 19-70 yrs affected by gonadotroph cell pituitary adenomas; the patients were studied by hormonal, radiological and immunohistochemical investigations and followed up for 3-13 yrs by ambulatory and/or hospitalized care. RESULTS: Visual impairment and/or decreased libido and erectile dysfunction were the symptoms at presentation. Increased serum gonadotropin concentrations were shown in 3 patients. Reduced levels of testosterone were present in 9 patients, and normal in the remainder. At diagnosis all patients had pituitary macroadenomas, with wide extrasellar extension in 12. All patients underwent trans-sphenoidal surgery and immunohistochemical staining of surgically excised specimens showed the presence of gonadotroph and alpha-subunit cells in all pituitary adenomas. After surgery 3 patients had clear radiological evidence of normal pituitary; in the others a doubtful MRI picture or a residual adenomatous tissue were present. In the patients who did not undergo radiotherapy immediately after surgery, a regrowth of tumoral tissue was shown in 1-10 yrs. CONCLUSIONS: We stress the importance of a close follow-up of patients with gonadotroph adenomas after surgery, and we raise the question of whether radiotherapy may be useful for avoiding any further adenomatous regrowth.

Naltrexone must not be considered a real therapy in functional hypothalamic amenorrhea. The results of a double blind controlled study.

Endogenous opioids exert a tonic inhibitory control on GnRH pulsatility at the hypothalamic level and it must be responsible for some hypogonadotropic hypogonadic syndromes such as functional hypothalamic amenorrhea (FHA). We treated 22 patients suffering from FHA with an oral anti-opioid drug, Naltrexone Hydrochloridrate (NH), 50 mg once a day or placebo, in a double blind controlled study. Six patients exhibited a regular resumption of their menstrual cycles (4 on placebo and only 2 on NH). There was an increase of 17BE2 in 3 of these 6 patients; progesterone levels did not change at all. Gynaecological echography demonstrated folliculogenesis in 4 of these 6 patients (only 1 on NH). The results show that NH is not a real therapy in patients suffering from FHA. Furthermore placebo, useful to the resumption of menstrual bleeding in 4 patients, underlines the importance of psychosomatic effects in the therapeutic management of FHA.

A new approach in the evaluation of gonadotropins for the diagnosis of polycystic ovary syndrome.

The new immunometric methods using monoclonal antibodies to detect gonadotropins revealed a reduction in the absolute values of these hormones, especially LH, due to a decrease in cross-reaction between gonadotropin subunits. Therefore, reference values of the LH/FSH ratio and their diagnostic significance in the polycystic ovary syndrome (PCOS) need to be defined again. We evaluated the LH/-FSH ratio in basal conditions and after administration of GnRH (100 micrograms as i.v. bolus) in seventy patients with PCOS employing an immunoenzymatic method. In PCOS patients the LH/FSH ratio was greater than 1 in 70% when evaluated on a single sample and in 88% when evaluated on a pooled serum from four samples every 30 minutes; in the control group the ratio was always lower than 1. The LH/-FSH ratio evaluated on the peak values in response to GnRH was greater than 2 in all patients and lower than 2 in the control group. Our results indicate that the LH/FSH ratio is still an important diagnostic tool in PCOS, especially when evaluated on the peak values in response to GnRH, even if its reference values are lower using these new monoclonal methods.

[Hormonal control of sexual behavior in males and endocrinologic causes of sexual dysfunction]. / Il controllo ormonale del comportamento sessuale nel maschio e cause endocrinologiche di disfunzione sessuale.

The role of androgens in the male sex differentiation, in the genesis and preservation of the erectile function is summarized. In sex differentiation, testosterone acts on genitalia and central nervous system (CNS). In CNS sexual steroids exert a morphogenetic action during neuronal development. At the pubertal age, the increase of testosterone leads to the development of sex characteristics, the onset of libido and the beginning of the nocturnal spontaneous erectile function. Spontaneous erections are androgen-dependent, and they are impaired in androgen deficiency. Normal androgen levels lead to make voluntary erections. However, in the human species, cortical influences may greatly affect what could be possible to occur in relation to the hormonal situation. Endocrine causes of sexual dysfunction are responsible for about 20-25% of the total; among these primary and secondary hypogonadisms are the most frequent and they are to be managed with causal treatments and androgen replacement therapy. Therefore, androgen treatments are not useful in functional sex disorders and they may be at risk on prostatic tissue. Andropause is related to a progressive reduction of testicular function, principally due to vascular disorders, with low-normal androgen levels. On the basis of these observations it is underlined that in the human species the androgen presence is a necessary but not sufficient condition for a correct sex function.

Feminine urinary incontinence and urodynamic examination.

The Authors performed urodynamic examinations on all patients affected by urinary incontinence. This examination enabled them to classify incontinence precisely, from the etiopathogenetic point of view. Incontinence may be due to an altered transmission of the abdominal pressure, to sphincteral lesions or insufficiency, or to stimuli. This classification provides clear indications for the choice of the most suitable therapy (surgical, medical, instrumental). It thereby contributes to improving the outcome and decreasing the number of relapses so far reported by all Authors using any of the suggested surgical techniques.

[Male fertility in the elderly]. / La fertilità maschile nella terza età.

Fertility in the elderly is still a less known argument. We report some news about seminal parameters (SP) and testicular hystological parameters (THP) in this age. About SP: the volume of the ejaculate, the number and the motility of spermatozoa are reduced. The morphology is typical: spermatozoa with coiled tails are common. About THP: some testes show a normal hystological architecture; others show a reduced volume and some aspects of hypospermatogenesis or maturative arrest; others show a very reduced volume, thickness of the tubular basal membrane and other signs of cellular regression. These signs are dependent upon the vascular insufficiency and the hormonal alterations which may occur in the elderly.

[International prostate symptom score: comparison of doctor and patient]. / International prostate symptom score: medico e paziente a confronto.

The AUA 7 score was originally designed and validated to be self administrated to patients with LUTS, its subsequent endorsement by the WHO - BPH committee made it the most widely used. Translation into different was provided and sometime validated. Aim of the study was to investigate the possibility to self administer the IPSS questionnaire to patients referred to our Institution for lower urinary tract symptoms. Two hundred and thirty-tree consecutive patients were given the IPSS questionnaire as a part of the routine diagnostic schedule; a senior resident was available to answer any possible question from the patient. After the form was returned, a second IPSS questionnaire was filled in by investigator following patient interview. Data were entered into an Excel database and the following parameters were investigate: number of forms completely filled in by patient, number of question answered in incomplete forms, degree of concordance between patient and investigator. One hundred and fifteen patients were able to fill the AUA 7 form completely; the quality of life question was answered by ninety-six patients only. Comparison of individual scores provided by the patient or assigned by the investigator showed a trend for the physician to underscore the patient problem for question 1-4 and to overestimate it in questions 5 to 7. At the lower range of the IPS score (0-7) no significant different between physician and patient was found. In the intermediate range (8-19) the physician tended to overestimate the patient symptoms. The reverse situations was found in the high score range (20-35). Globally, there was a trend for the patient score to be higher than the one assigned by the investigator, Doctor IPSS and quality of life scores appeared to be significantly related. No relation was found between doctor IPSS and the degree of bladder outlet obstruction as measured by parameter of pressure-flow study and diagnostic nomograms. The IPSS form appeared to be a difficult questionnaire for our patients and less than half of them were able to fill it in properly. Overall, the investigators tended to underestimate the patient voiding disturbances. Careful linguistic review of the Italian version of the IPSS questionnaire is required to make self evaluation of patient symptom possible. Symptom grading by a trained investigator did not seem to introduce any significant bias which might be of importance for the sake of clinical trials.

[The Studer orthotopic ileal neobladder: patient compliance]. / Neovesciche ileali ortotopiche sec. Studer: "compliance" del paziente.

Radical cystectomy represents the gold standard for locally advanced bladder cancer. Orthotopic neobladder is considered the surgical option which may offer the least modification of body image and the best life condition to the unfortunate patient requiring radical cystectomy. Objective of this study was to investigate long term clinical outcome of orthotopic ileal bladder substitute with special reference to late complications and patient compliance. Twenty male patients 48 to 71 years old (mean age 59.8 + 7.4 years) underwent radical cystectomy and Studer orthotopic ileal neobladder for invasive carcinoma of the bladder. Before surgery all patients filled in a phycometric test for evaluating their knowledge capacity; after surgery they underwent a course of biofeedback and instructed to avoid overfilling of the neobladder with timed micturitions and a regular regimen of fluid intake. Pressure flow study was included in the routine follow-up carried out at six months and then yearly. Seventeen patients (85%), with a good knowledge capacity, reported a good compliance to the modified life style imposed by the bladder substitute, they all were dry during the day with 3 to 5.5 hour interval between micturitions; fourteen of these patients were continent at night with timed micturitions every 3-4 hours (mean: 3.2); an average cystometric capacity of 450 ml was found in these patients with no residual urine; three patients (18%) had incontinence episodes once or twice a week during the night; no decompensation of the neobladder, significant ureteral reflux or dilatation were reported; elongation of the afferent loop was found in one patient following small bowel resection for ileal volvulus. Three patients (15%), with a reduced knowledge capacity, who did not follow the suggested life style: fluid intake was irregular, micturitions were not timed during both day and night time, had residual urine larger than 400 ml. and incontinence episodes requiring pads; nevertheless no dilation of the upper urinary tract was found. Our experience suggests that careful compliance of patients to the new life style imposed by the orthotopic neobladder is of importance to avoid its decompensation. The possible causative role of gastrointestinal hormones such as enteroglucagon (EG) and peptide tyrosine-tyrosine (PYY) in the elongation of the afferent limb of the Studer neobladder is proposed. In conclusion, we believe that orthotopic ileal neobladder is an ideal surgical option on in the young, educated and cooperative patients.