Validity of free testosterone calculation in pregnant women.

Objective Increased maternal testosterone concentration during pregnancy may affect the fetus. Therefore it is clinically relevant to have a quick and reliable method to determine free testosterone levels. Current calculators for free testosterone are suspected to perform poorly during pregnancy due to suggested competition between high levels of estradiol and free (bio-active) testosterone for sex hormone-binding globulin (SHBG) binding. Therefore, it is claimed that reliable calculation of free testosterone concentration is not possible. However, recent evidence on SHBG-binding sites questions the estradiol effect on the testosterone-SHBG binding during pregnancy. In this study, we investigated whether the free testosterone concentration can be calculated in pregnant women. Design and methods Free testosterone was measured with a specially developed equilibrium dialysis method combined with liquid chromatography tandem mass spectrometry (LC-MS/MS). Free testosterone was also calculated with the formulas of Vermeulen et al. and Ross et al. Results Total and free testosterone measured in healthy men and women were in good agreement with earlier reports. In pregnant women, total testosterone values were higher than in non-pregnant women, whereas free testosterone values were comparable. Calculated free testosterone levels in pregnant women were highly correlated, but marginally higher, compared to measured free testosterone levels. Conclusions We developed an equilibrium dialysis-LC-MS/MS method for the measurement of free testosterone in the low range of pregnant and non-pregnant women. Although during pregnancy total testosterone is increased, this is not the case for free testosterone. The free testosterone formulas perform well in pregnant women.

Gonadal function in adult male patients with congenital adrenal hyperplasia.

CONTEXT: Current knowledge on gonadal function in congenital adrenal hyperplasia (CAH) is mostly limited to single-center/country studies enrolling small patient numbers. Overall data indicate that gonadal function can be compromised in men with CAH. OBJECTIVE: To determine gonadal function in men with CAH within the European 'dsd-LIFE' cohort. DESIGN: Cross-sectional clinical outcome study, including retrospective data from medical records. METHODS: Fourteen academic hospitals included 121 men with CAH aged 16-68 years. Main outcome measures were serum hormone concentrations, semen parameters and imaging data of the testes. RESULTS: At the time of assessment, 14/69 patients had a serum testosterone concentration below the reference range; 7 of those were hypogonadotropic, 6 normogonadotropic and 1 hypergonadotropic. In contrast, among the patients with normal serum testosterone (55/69), 4 were hypogonadotropic, 44 normogonadotropic and 7 hypergonadotropic. The association of decreased testosterone with reduced gonadotropin concentrations (odds ratio (OR) = 12.8 (2.9-57.3)) was weaker than the association between serum androstenedione/testosterone ratio ≥1 and reduced gonadotropin concentrations (OR = 39.3 (2.1-732.4)). Evaluation of sperm quality revealed decreased sperm concentrations (15/39), motility (13/37) and abnormal morphology (4/28). Testicular adrenal rest tumor (TART)s were present in 39/80 patients, with a higher prevalence in patients with the most severe genotype (14/18) and in patients with increased current 17-hydroxyprogesterone 20/35) or androstenedione (12/18) serum concentrations. Forty-three children were fathered by 26/113 patients. CONCLUSIONS: Men with CAH have a high risk of developing hypothalamic-pituitary-gonadal disturbances and spermatogenic abnormalities. Regular assessment of endocrine gonadal function and imaging for TART development are recommended, in addition to measures for fertility protection.

Endoscopic transsphenoidal pituitary surgery: a good and safe primary treatment option for Cushing's disease, even in case of macroadenomas or invasive adenomas.

CONTEXT: Although the endoscopic technique of transsphenoidal pituitary surgery (TS) has been widely adopted, reports on its results in Cushing's disease (CD) are still scarce and no studies have investigated long-term recurrence rates. This is the largest endoscopic series published till now. OBJECTIVE: To gain insight into the role of endoscopic TS as a primary treatment option for CD, especially in patients with magnetic resonance imaging (MRI)-negative CD and (invasive) macroadenomas. DESIGN: Retrospective cohort study. PATIENTS AND METHODS: The medical records of 86 patients with CD who underwent endoscopic TS were examined. Data on preoperative and postoperative evaluation, perioperative complications, and follow-up were collected. Remission was defined as disappearance of clinical symptoms with a fasting plasma cortisol level ≤ 50 nmol/l either basal or after 1 mg dexamethasone. RESULTS: The remission rate in different adenoma subclasses varied significantly: 60% in MRI-negative CD (n=20), 83% in microadenomas (n=35), 94% in noninvasive macroadenomas (n=16), and 40% in macroadenomas that invaded the cavernous sinus (n=15). The recurrence rate was 16% after 71 ± 39 months of follow-up (mean ± S.D., range 10-165 months). CONCLUSIONS: Endoscopic TS is a safe and effective treatment for all patients with CD. Recurrence rates after endoscopic TS are comparable with those reported for microscopic TS. Our data suggest that in patients with noninvasive and invasive macroadenomas, the endoscopic technique of TS should be the treatment of choice as remission rates seem to be higher than those reported for microscopic TS, although no comparative study has been performed.

Congenital adrenal hyperplasia--pharmacologic interventions from the prenatal phase to adulthood.

Congenital adrenal hyperplasia (CAH) is one of the most common inherited autosomal recessive disorders, caused by deficiency of one of the enzymes involved in steroid synthesis. The clinical picture of the most prevalent form, i.e. 21-hydroxylase deficiency, is characterized by cortisol and mostly aldosterone deficiency and androgen excess (leading to congenital virilization in girls). Treatment consists of glucocorticoids, aimed at substitution of cortisol deficiency and, decrease of androgen excess. Usually supraphysiological doses of glucocorticoids are required to effectively suppress adrenal androgens. Furthermore, with the currently available glucocorticoid preparations, it is not possible to simulate a normal circadian rhythm in CAH patients. Therefore, it is a difficult task for (pediatric) endocrinologists to find the best balance between under- and overtreatment thereby avoiding important long term complications. In this review we will discuss the current pharmacologic treatment options. We give age dependent dose recommendations and describe the limitations of current treatment strategies. We discuss effects on fertility, bone density and cardiovascular risks. Recommendations about the use of glucocorticoids in case of fever or stress situations are given. The principles of treatment of non classic (mild) CAH are discussed in a separate section. Also prenatal therapy, to prevent congenital virilization of a female CAH newborn, is discussed. Furthermore, an overview of alternative pharmacological treatment options in the future is given.

Fertility in patients with congenital adrenal hyperplasia.

Congenital adrenal hyperplasia (CAH) is generally regarded as a paediatric endocrine disease, but nowadays nearly all patients reach adulthood as a result of improved diagnosis and treatment. It is now increasingly recognised that treatment goals shift during life: one of the major treatment goals in childhood and puberty, i.e. normal growth and development, is no longer relevant after childhood, whereas other aspects, such as fertility and side effects of long-term glucocorticoid treatment, become more important in adulthood. This paper focuses on fertility in male and female adult patients with CAH. In males with CAH the fertility rate is reduced compared with the normal population, the most frequent cause being testicular adrenal rest tumours. Development and growth of these tumours is assumed to be ACTH dependent and undertreatment may play an important role. If intensifying glucocorticoid treatment does not lead to tumour decrease, surgical intervention may be considered, but the effect on fertility is not yet known. In females with CAH the degree of fertility depends on the phenotype of the CAH. Most fertility problems are seen in the classic salt-wasting type. Age of menarche and regularity of the menstrual cycle depends on the degree of adrenal suppression. Not only adrenal androgens have to be normalised but also the levels of adrenal progestins (progesterone and 17-OH-progesterone) that interfere with normal ovulatory cycles. The regularity of menstrual cycles can be considered as an important measure of therapeutic control in adolescent females with CAH and therefore as a therapeutic goal from (peri)pubertal years on. Other factors that contribute to impaired fertility in females with CAH are ovarian hyperandrogenism (polycystic ovary syndrome), ovarian adrenal rest tumours, genital surgery and psychological factors. Subfertility in CAH can have its origin already in the peripubertal years and is therefore of interest to the paediatric endocrinologist.