Androgens in women either derive from direct ovarian production or from peripheral conversion of the adrenal sex steroid precursor, dehydroepiandrosterone, towards active androgens. Therefore, loss of adrenal or ovarian function, caused by Addison’s disease or consequent to bilateral oophorectomy, results in severe androgen deficiency, clinically often associated with a loss of libido and energy. Importantly, physiological menopause does not necessarily lead to androgen deficiency, as androgen synthesis in the ovaries may persist despite the decline in estrogen production. However, the definition of female androgen deficiency, as recently provided by the Princeton consensus statement, is not precise enough and may lead to over-diagnosis due to the high prevalence of its diagnostic criteria: androgen levels below or within the lower quartile of the normal range and concurrent sexual dysfunction. Importantly, physiological menopause is not necessarily associated with androgen deficiency and therefore does not routinely require androgen therapy. Current replacement options include transdermal testosterone administration or dehydroepiandrosterone treatment, both of which have been shown to result in significant improvements, in particular in libido and mood, while effects on body composition and muscular function are not well documented. It is important to keep in mind that the number of randomized controlled trials is still limited and that currently none of the available preparations is officially approved for use in women. Currently, androgen replacement should be reserved for women with severe androgen deficiency due to an established cause and matching clinical signs and symptoms.
Katherine White and Wiebke Arlt
Adrenal crisis is a life-threatening event that occurs regularly in Addison's patients receiving standard replacement therapy. Patient reports suggest that it is an underestimated and under-managed event.
To assess the frequency of adrenal crisis in diagnosed patients and to understand the factors contributing to the risks of adrenal crisis.
We conducted a postal survey of Addison's patients in four countries, UK (n=485), Canada (n=148), Australia (n=123) and New Zealand (n=85) in 2003, asking about patients' experiences of adrenal crisis and their demographic characteristics. In 2006, a shorter follow-up survey was conducted in the UK (n=261).
The frequency and causes of adrenal crisis were compared across both surveys. Demographic data from the 2003 survey were analysed to establish the main variables associated with an elevated risk of crisis.
Around 8% of diagnosed cases can be expected to need hospital treatment for adrenal crisis annually. Exposure to gastric infection is the single most important factor predicting the likelihood of adrenal crisis. Concomitant diabetes and/or asthma increase the frequency of adrenal crises reported by patients.
The endocrinologist has a responsibility to ensure that Addison's patients have adequate access to life-saving emergency injection materials and repeated, practical training sessions in how to use them, while the general practitioner plays a vital role as in arranging prompt emergency admissions.
Lina Schiffer, Punith Kempegowda, Wiebke Arlt and Michael W O’Reilly
Female androgen excess and male androgen deficiency manifest with an overlapping adverse metabolic phenotype, including abdominal obesity, insulin resistance, type 2 diabetes mellitus, non-alcoholic fatty liver disease and an increased risk of cardiovascular disease. Here, we review the impact of androgens on metabolic target tissues in an attempt to unravel the complex mechanistic links with metabolic dysfunction; we also evaluate clinical studies examining the associations between metabolic disease and disorders of androgen metabolism in men and women. We conceptualise that an equilibrium between androgen effects on adipose tissue and skeletal muscle underpins the metabolic phenotype observed in female androgen excess and male androgen deficiency. Androgens induce adipose tissue dysfunction, with effects on lipid metabolism, insulin resistance and fat mass expansion, while anabolic effects on skeletal muscle may confer metabolic benefits. We hypothesise that serum androgen concentrations observed in female androgen excess and male hypogonadism are metabolically disadvantageous, promoting adipose and liver lipid accumulation, central fat mass expansion and insulin resistance.
Dorota Tomalik-Scharte, Dominique Maiter, Julia Kirchheiner, Hannah E Ivison, Uwe Fuhr and Wiebke Arlt
Patients with congenital adrenal hyperplasia due to P450 oxidoreductase (POR) deficiency (ORD) present with disordered sex development and glucocorticoid deficiency. This is due to disruption of electron transfer from mutant POR to microsomal cytochrome P450 (CYP) enzymes that play a key role in glucocorticoid and sex steroid synthesis. POR also transfers electrons to all major drug-metabolizing CYP enzymes, including CYP3A4 that inactivates glucocorticoid and oestrogens. However, whether ORD results in impairment of in vivo drug metabolism has never been studied.
We studied an adult patient with ORD due to homozygous POR A287P, the most frequent POR mutation in Caucasians, and her clinically unaffected, heterozygous mother. The patient had received standard dose oestrogen replacement from 17 until 37 years of age when it was stopped after she developed breast cancer.
Both subjects underwent in vivo cocktail phenotyping comprising the oral administration of caffeine, tolbutamide, omeprazole, dextromethorphan hydrobromide and midazolam to assess the five major drug-metabolizing CYP enzymes. We also performed genotyping for variant CYP alleles known to affect drug metabolism.
Though CYP enzyme genotyping predicted normal or high enzymatic activities in both subjects, in vivo assessment showed subnormal activities of CYP1A2, CYP2C9, CYP2D6 and CYP3A4 in the patient and of CYP1A2 and CYP2C9 in her mother.
Our results provide in vivo evidence for an important role of POR in regulating drug metabolism and detoxification. In patients with ORD, in vivo assessment of drug-metabolizing activities with subsequent tailoring of drug therapy and steroid replacement should be considered.
Anna C Phillips, Douglas Carroll, Catharine R Gale, Janet M Lord, Wiebke Arlt and G David Batty
The aim of these analyses was to examine the association of cortisol, DHEAS and the cortisol:DHEAS ratio with the metabolic syndrome (MetS) and its components.
The analyses were cross-sectional.
Participants were 4255 Vietnam era US army veterans. From military service files, telephone interviews and a medical examination, occupational, socio-demographic and health data were collected. MetS was ascertained from data on body mass index; fasting blood glucose or a diagnosis of diabetes; blood pressure or a diagnosis of hypertension; high-density lipoprotein cholesterol; and triglyceride levels. Contemporary morning fasted cortisol and DHEAS concentrations were determined. The outcomes were MetS and its components. Analysis was by logistic regression, first adjusting for age and then additionally for an array of candidate confounders.
Cortisol, although not in the fully adjusted analysis, and DHEAS were both related to MetS. Whereas high cortisol concentrations were associated with an increased risk of MetS, high DHEAS concentrations appeared protective. By far, the strongest associations with MetS were observed for the cortisol:DHEAS ratio; the higher the ratio, the greater the risk of having MetS. The ratio was also significantly related to four of the five MetS components.
The cortisol:DHEAS ratio is positively associated with MetS. Prospective analyses are needed to help untangle direction of causality, but this study suggests that the cortisol:DHEAS ratio is worthy of further study in this and other health contexts.
Irina Bancos, Jon Hazeldine, Vasileios Chortis, Peter Hampson, Angela E Taylor, Janet M Lord and Wiebke Arlt
Mortality in patients with primary adrenal insufficiency (PAI) is significantly increased, with respiratory infections as a major cause of death. Moreover, patients with PAI report an increased rate of non-fatal infections. Neutrophils and natural killer (NK) cells are innate immune cells that provide frontline protection against invading pathogens. Thus, we compared the function and phenotype of NK cells and neutrophils isolated from PAI patients and healthy controls to ascertain whether altered innate immune responses could be a contributory factor for the increased susceptibility of PAI patients to infection.
Design and methods
We undertook a cross-sectional study of 42 patients with PAI due to autoimmune adrenalitis (n = 37) or bilateral adrenalectomy (n = 5) and 58 sex- and age-matched controls. A comprehensive screen of innate immune function, consisting of measurements of neutrophil phagocytosis, reactive oxygen species production, NK cell cytotoxicity (NKCC) and NK cell surface receptor expression, was performed on all subjects.
Neutrophil function did not differ between PAI and controls. However, NKCC was significantly reduced in PAI (12.0 ± 1.5% vs 21.1 ± 2.6%, P < 0.0001). Phenotypically, the percentage of NK cells expressing the activating receptors NKG2D and NKp46 was significantly lower in PAI, as was the surface density of NKG2D (all P < 0.0001). Intracellular granzyme B expression was significantly increased in NK cells from PAI patients (P < 0.01).
Adrenal insufficiency is associated with significantly decreased NKCC, thereby potentially compromising early recognition and elimination of virally infected cells. This potential impairment in anti-viral immune defense may contribute to the increased rate of respiratory infections and ultimately mortality in PAI.
Anna C Phillips, Douglas Carroll, Catharine R Gale, Janet M Lord, Wiebke Arlt and G David Batty
The aim of the present analyses was to examine the association between cortisol, DHEA sulphate (DHEAS) and the cortisol:DHEAS ratio and mortality.
This was a prospective cohort analysis.
Participants were 4255 Vietnam-era US army veterans. From military service files, telephone interviews and a medical examination, occupational, socio-demographic and health data were collected. Contemporary morning fasted cortisol and DHEAS concentrations were determined. Mortality was tracked over the subsequent 15 years. The outcomes were all-cause, cardiovascular disease, cancer, other medical mortality and external causes of death. Cox proportional hazard models were tested, initially with adjustment for age, and then with adjustment for a range of candidate confounders.
In general, cortisol concentrations did not show an association with all-cause or cause-specific mortality. However, in age-adjusted and fully adjusted analyses, DHEAS was negatively related to all-cause, all cancers and other medical mortality; high DHEAS concentrations were protective. The cortisol:DHEAS ratio was also associated with these outcomes in both age-adjusted and fully adjusted models; the higher the ratio, the greater the risk of death.
DHEAS was negatively associated, and the ratio of cortisol to DHEAS was positively associated with all-cause, cancer and other medical cause mortality. Further experimental study is needed to elucidate the mechanisms involved in these relationships.
Jan Idkowiak, Gareth G Lavery, Vivek Dhir, Timothy G Barrett, Paul M Stewart, Nils Krone and Wiebke Arlt
Adrenarche reflects the maturation of the adrenal zona reticularis resulting in increased secretion of the adrenal androgen precursor DHEA and its sulphate ester DHEAS. Premature adrenarche (PA) is defined by increased levels of DHEA and DHEAS before the age of 8 years in girls and 9 years in boys and the concurrent presence of signs of androgen action including adult-type body odour, oily skin and hair and pubic hair growth. PA is distinct from precocious puberty, which manifests with the development of secondary sexual characteristics including testicular growth and breast development. Idiopathic PA (IPA) has long been considered an extreme of normal variation, but emerging evidence links IPA to an increased risk of developing the metabolic syndrome (MS) and thus ultimately cardiovascular morbidity. Areas of controversy include the question whether IPA in girls is associated with a higher rate of progression to the polycystic ovary syndrome (PCOS) and whether low birth weight increases the risk of developing IPA. The recent discoveries of two novel monogenic causes of early onset androgen excess, apparent cortisone reductase deficiency and apparent DHEA sulphotransferase deficiency, support the notion that PA may represent a forerunner condition for PCOS. Future research including carefully designed longitudinal studies is required to address the apparent link between early onset androgen excess and the development of insulin resistance and the MS.
Vasileios Chortis, Nicholas J Johal, Irina Bancos, Matthew Evans, Kassiani Skordilis, Peter Guest, Michael H Cullen, Emilio Porfiri and Wiebke Arlt
Mitotane (o,p′DDD) is established in the adjuvant and advanced-stage treatment of adrenocortical carcinoma and counteracts both tumor growth and tumor-related steroid production. Both the adrenal glands and the gonads are steroidogenically active organs and share a common embryogenic origin. Here, we describe the effects of mitotane in two patients with metastatic Leydig cell tumor (LCT) of the testes and associated severe androgen excess (serum testosterone 93 and 88 nmol/L, respectively; male reference range 7–27 nmol/L). Both men suffered from severe restlessness, insomnia and irritability, which they described as intolerable and disrupting normal life activities. Urinary steroid profiling by gas chromatography–mass spectrometry (GC–MS) confirmed excess androgen production and revealed concurrent overproduction of glucocorticoids and glucocorticoid precursors, which under physiological conditions are produced only by the adrenal glands but not by the gonads. In a palliative approach, they were commenced on mitotane, which achieved swift control of the hormone excess and the debilitating clinical symptoms, restoring normal quality of life. GC–MS demonstrated normalization of steroid production and decreased 5α-reductase activity, resulting in decreased androgen activation, and imaging demonstrated disease stabilization for 4–10 months. In conclusion, mitotane can be highly effective in controlling steroid excess in metastatic LCTs, with anti-tumor activity in some cases.