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Journal of Medical Cases

Case Report

Volume 4, Number 8, August 2013, pages 569-575

Effect of Vitamin D in a Patient With Classical Adrenal Hyperplasia due to 11-Hydroxylase Deficiency

Congenital Adrenal hyperplasia (CAH) is an autosomal dominant disorder with variable penetrance caused by a quantitative or functional deficiency of enzymes required for the synthesis of cortisol and/or aldosterone in the adrenal glands. The most common adrenal enzyme deficiency is 21-hydroxylase deficiency (21-OHD), while 11-hydroxylase deficiency (11OHD) accounts for approximately 5 - 8% of cases [1, 2]. In the adrenal gland during the final step of cortisol synthesis, 11-hydroxylase converts 11- deoxycortisol (compound S) to cortisol. In patients with 11OHD, ACTH secretion from the pituitary is increased due to decreased negative feedback from cortisol on hypothalamic CRH secretion. This leads to formation of more cortisol precursors, which are then siphoned off towards androgen production leading to hyperandrogenism.

Patients with CAH are grouped into two major categories depending on the severity of the enzyme deficiency. There is a classical form in which symptoms are evident at birth with virilization and external genital ambiguity in female infants, hypertension in infants with classical 11-OHD, and salt-wasting with hypotension in some infants with classic 21-OHD [3]. There is also a non-classical form, which does not become apparent until later in life, since it is due to a milder mutation or to a more severe mutation that is heterozygously expressed. These patients usually present in mid-childhood, adolescence, or adulthood with acne, irregular menses, infertility, hirsutism, and precocious pubarche [4]. Additionally, CAH is also associated with conditions such as obesity, autoimmunity [5] and insulin resistance (IR) [6]. It has been reported that IR may also be associated with vitamin D deficiency [7].

In recent years, vitamin D deficiency has been recognized as a global concern [8]. 10 - 60% of all adults worldwide have vitamin D deficiency/insufficiency [8]. Vitamin D deficiency is currently defined as serum 25-hydroxyvitamin D (25(OH) D) levels less than 20 ng/mL, while insufficiency is defined as levels between 20 to 30 ng/mL, and severe deficiency at levels < 10 ng/mL. Vitamin D replete is defined as values above 30 ng/mL due to lack of physiological (negative feedback) response of PTH to vitamin D at concentrations above this value in women [9]. Some of the purported non-classic benefits of Vitamin D, e.g. insulin sensitization and improved insulin secretion, anti-neoplastic, cardiovascular, and immunomodulatory may require somewhat higher levels of Vitamin D [10-17].

Vitamin D inadequacy has been associated with a variety of conditions such as, osteoporosis [18], falls [19] cardiovascular disease [20], systemic lupus erythematosus [21], diabetes mellitus type I [22], preeclampsia [23], multiple sclerosis [24], tuberculosis [25], breast cancer [26], and colorectal cancer [27]. Recent studies have also linked vitamin D deficiency to IR [28]. Various conditions that are associated with IR have also been reported to be affected by vitamin D levels [29-32]; of particular interest here is Polycystic Ovarian Syndrome (PCOS), which shares many features with NCAH, including IR [32].

These shared features include: hyperandrogenism, menstrual irregularities, hypofertility, polycystic ovaries, central obesity, acanthosis, skin tags, premature pubarche, and IR. Many interventions that ameliorate PCOS also improve the biochemical and clinical expression of NCAH. Recently, Vitamin D deficiency has been linked to more severe expression of PCOS symptoms and its supplementation has been shown to be beneficial in improving a variety of PCOS symptoms such as menstrual abnormalities and IR [32]. Although various studies have explored the role of vitamin D in the treatment of PCOS, the potential therapeutic value of vitamin D for congenital adrenal hyperplasia (CAH) has not been extensively explored. In this case report, we present and discuss what appears to be the first reported case of classical 11OHD biochemically improved with vitamin D supplementation alone.

Our patient is an obese 47 years old male (as per his own gender identification) with hypertension and diabetes mellitus type 2, who was hospitalized for cellulitis, abscess, osteomyelitis, and gangrene of the left foot. He does not have any progeny, but per him, he did not want any children. On further questioning he denied ever having had sexual relations. He denied any recent history of acne. On physical examination he is 178 cm (5’10”) tall and has a BMI of 36.45 kg/m² with a central fat distribution. He has a stage IVa Hamilton male pattern alopecia that started during his 20’s [33].

There is no acanthosis nigricans or hyperpigmentation. He has microphallus (or clitoromegaly?), measuring 2.0 cm in length. His mother related that he underwent surgical correction of hypospadias in early childhood. His testes were fully descended and measured 3.4 cm in their longer diameter. Since the patient refused scrotal ultrasound, we do not know if the testis were natural or prosthetic or if the “scrotum” contained adrenal rests. The patient’s mother was unable to supply any additional information on this point.

On further investigation his unstimulated 0800 serum 11-deoxycortisol by liquid chromatography tandem mass spectroscopy (LC MS/MS) was 2024 ng/dL ( ≤ 76) while his serum 25OHD was 12 ng/mL (≥ 30) (Fig. 1). Unstimulated 0800 levels of 17-OH-progestesterone, 17-OH-pregnenolone, and deoxycorticosterone were normal. Supplementation was begun with ergocalciferol 50,000 units orally weekly. After 9 days his serum 25OHD rose to 23 ng/mL while his serum 11-deoxycortisol fell to 425 ng/dL. Seventeen days after beginning supplementation his serum 25OHD further improved to 27 ng/dL while his 11-deoxycortisol improved to 194 ng/dL (Fig. 1). Twenty-nine days after starting ergocalciferol the 11-deoxycortisol level fell to < 20 ng/dl; the sample for the corresponding 25-OHD was lost by the laboratory. We believed our patient might be a genetically female pseudohermaphrodite. A lymphocyte karyotype was performed, which was XY with normal G-band patterns within the limits of standard cytogenetic analysis. The following possibilities, although rare, could not be ruled out: low level mosaicism, very subtle rearrangements, and genetic disorders undetectable by standard cytogenetic methods. The patient declined further investigation, such as skin or testicular biopsy for karyotyping. He was subsequently discharged to a rehabilitation facility.

Click for large image

Figure 1. Changes in serum 11-deoxycortisol (left) as a function of changes in serum 25-OH-Vitamin D (right) at baseline and at 9 days and 17 days after starting ergocalciferol 50,000 IU daily.

In recent years there has been significant interest regarding “non-classic” roles of vitamin D after it was discovered that, in addition to kidneys, bone and gut, vitamin D receptors are also present in other tissues such as brain, prostate, breast, colon, adrenal cortex, and immune cells [32, 11, 34-36]. Since most tissues and cells in the body have a vitamin D receptor and 1, 25 (OH) 2D influences the expression levels along with other factors of up to one third of the human genome [37], an area that has been the focus of some research has been the relationship between vitamin D and IR. Animal studies have shown that supplementation of vitamin D increases secretion of insulin and improves insulin sensitivity [38]. Afsaneh et al. reported an inverse relation between fasting plasma glucose and basal 25(OH) vitamin D level, and only higher vitamin D concentrations of 40 - 60 ng/mL are associated with improvement in insulin sensitivity [39]. Inzucchi et al. reported increased insulin sensitivity in 54% of 5677 subjects by vitamin D supplementation [40]. Additionally, various studies have shown that vitamin D supplementation in conditions that are associated with IR, such as diabetes type 2, metabolic syndrome, PCOS, and hepatitis C, may be beneficial [29-32, 41]. In recent years, it has also been reported that CAH is also associated with IR [6, 42-46].

Non-classical 21-OHD is one of the most common autosomal disorders with the highest prevalence amongst Hispanics, eastern European Jews, and Mediterraneans [47] accounting for 90% of reported cases of NCAH. The disorder is due to mutations of the CYP21A2 gene located at chromosome 6p21 in the HLA locus. In 1951 Shepard and Clausen reported a less common type of CAH resulting from 11OHD, which is the type presented in this case report [3]. The incidence of 11OHD in the general population is 1/100,000, while its frequency has been reported as high as 1/5000 in highly inbred populations such as Moroccan Jews [48].

Biochemically, classical 11OHD patients usually have baseline elevations of plasma ACTH, which then leads to increased formation of ACTH-stimulated cortisol precursors such as 11-deoxycortisol and others. Some of these precursors will then accumulate and subsequently are shunted off to the androgen synthesis pathway leading to elevated androgen levels. Clinically, the classical form of 11OHD often presents in newborn females with ambiguous genitalia and hypertension; male infants might have hypertension and appear excessively virilized, while the non-classic form presents later in life as precocious pubarche, hirsutism, acne, alopecia, infertility, and menstrual abnormalities. Final adult height may be compromised due to early epiphyseal closure.

Conventional treatment of 11OHD varies by age and sex, but is mainly focused on glucocorticoids, which inhibit the central secretion of corticotrophin releasing hormone (CRH) and ACTH, resulting in a decrease in androgen precursors and subsequent androgen synthesis. Treatment goals include normal linear growth velocity and “on-time” puberty in affected children. In adolescent and adult females treatment is aimed at regularization of menses, amelioration of hirsutism, acne, and alopecia, and restoration of fertility [49]. A consensus now recommends that hydrocortisone be used in the treatment of children with CAH, rather than long-acting glucocorticoids like dexamethasone [50-54]. Infants with ambiguous genitalia may undergo corrective surgery to render the phenotypic gender congruent with the chromosomal sex. Such surgery should be performed before the child’s gender identity has been established. In pregnancies in which the offspring are at high risk for classical 21-OHD, pre-natal treatment with dexamethasone has been reported to be effective in preventing the birth of female babies with ambiguous genitalia [55-57]. Although glucocorticoid treatment (sometimes combined with fludrocortisone) continues to be the mainstay of conventional treatment of CAH and has been very helpful and lifesaving in that capacity, its use, even with recent refinements, continues to be plagued with issues regarding over- and under-treatment, growth inhibition, hypertension, obesity, low bone density, testicular adrenal rest tumors, and diabetes [58-60]. Our group has been focusing on insulin sensitizing interventions to reduce IR, which is a consistent feature of CAH, as it is with PCOS [61-65].

It has been reported that CAH is associated with IR [6]. In vitro studies have shown that hyperinsulinemia may direct the adrenals toward androgen synthesis and away from cortisol production [66]. Charmandari et al. showed that children with CAH, when compared to normal children matched for BMI, are more likely to have IR [44]. Recently, Finkielstain et al. conducted a cross-sectional study of 244 patients with both classical and non-classical adrenal hyperplasia and reported that IR was present in 38% and 20% of adults with classical and non-classical adrenal hyperplasia respectively, and furthermore, 61% of all these patients were vitamin D insufficient [46]. In this study assessment for insulin resistance was performed using only HOMA-IR, which reflects hepatic insulin resistance to a greater degree than peripheral (fat/muscle) insulin resistance. The role of vitamin D in PCOS, a condition that closely resembles NCAH, has been the subject of extensive research in recent years.

Various studies have shown that Vitamin D supplementation may be beneficial in PCOS patients, possibly owing to its insulin sensitizing effect. Patra et al. showed that PCOS patients who were also vitamin D deficient had more severe IR [67]. This study demonstrated a strong inverse relationship between serum 25(OH) vitamin D level and obesity in PCOS patients, which may be explained by the storage of lipophilic 25(OH) vitamin D in adipose tissue. Vitamin D with calcium and metformin could be effective for the treatment of anovulation and oligomenorrhea in PCOS [68]. Selimoglu et al. treated 11 women with PCOS, nine of whom were vitamin D deficient, with single doses of vitamin D3 (300,000 IU) orally and showed a significant decrease in homeostasis model assessment (HOMA)-IR and serum androgen levels after only 3 weeks [69]. The precise mechanism behind vitamin D’s effect on insulin sensitization is unknown, however, it has been suggested that it might be due to increased synthesis and release of insulin (which can reduce the IR secondary to glucose toxicity), enhanced insulin receptor expression (by regulating nuclear peroxisome proliferator activated receptor gamma [PPAR-γ]), an effect on calcium and phosphorous metabolism, or due to inhibition of inflammatory cytokines IL-1, IL-6, and TNF-α that may be involved in the development of IR [70].

Besides insulin sensitization, vitamin D has immunomodulatory effects. NCAH is also associated with autoimmunity [5]. Administration of the active vitamin D metabolite, calcitriol, ameliorates experimental autoimmune diseases such as type 1 diabetes and thyroiditis. On the molecular level 1, 25(OH2) D3 supplementation leads to decreased expression of HLA class 2 molecules on endocrine cells and inhibits T cell proliferation and secretion of cytokines. An effect of vitamin D on thymic education (‘hormonal imprinting’) has been reported in animals, which also contributes to its immunomodulatory properties. Vitamin D levels are lower in auto-immune hyperthyroidism than in non-autoimmune hyperthyroidism. Also Vitamin D supplementation in infancy was reported to be associated with a lower incidence of type 1 diabetes. The actions of 1, 25 (OH) 2D3 are mediated via the nuclear vitamin D receptor. Certain polymorphisms of its gene, located on chromosome 12q12-14, were found to be associated with autoimmune diseases such as type 1 diabetes, Graves’ disease, Crohn’s disease, rheumatoid arthritis, systemic lupus [17] and Addison’s disease [35].

It has been also shown that Vitamin D deficiency leads to increased parathyroid hormone (PTH) levels. Increased PTH levels alone have been associated with increased testosterone, infertility, and IR, most of which are present in both NCAH and PCOS [32, 70-71]. Bachelot et al. suggested that maintaining vitamin D sufficiency should be a goal for individuals with CAH [72]. Hence, CAH patients with vitamin D deficiency may benefit from vitamin D supplementation to reduce their symptoms and biochemical abnormalities, although evidence from randomized clinical trials is needed to confirm its possible therapeutic value. Here we reported a case in which vitamin D supplementation was associated with dramatically reduced 11-deoxycortisol levels in a patient with 11OHD and vitamin D deficiency. We conclude that vitamin D supplementation might be an alternative means of treating CAH due to 11OHD in patients who also have vitamin D deficiency/insufficiency, and propose that it may work indirectly by reducing IR and by immunomodulation whereby any autoimmune assault on the steroidogenic machinery of the adrenal cortex may be ameliorated via reduction in cytokine production, downregulation of T cell proliferation, and downregulation of expression of HLA-Class II molecules involved in the suppression of synthesis and activity of adrenal steroidogenic enzymes. Vitamin D supplementation may work directly in CAH via binding to the adrenocortical vitamin D receptors affecting the synthesis and expression of adrenocortical steroidogenic enzymes via cross-talk.

The dramatic and rapid reduction in serum 11-deoxycortisol associated with Vitamin D repletion.

1) Data is only available for one classical 11-OHD patient.

2) It is unknown if some of the likely improvement in insulin sensitivity in this patient with the resulting impressive decline in serum 11-deoxycortisol was due to factors other than Vitamin D repletion, e.g. control of infection via surgery and antibiotics as well as reduction in glycemia due to control of infection, nutritional therapy, and insulin, with a reduction in the IR resulting from glucose toxicity.

3) It is unknown whether our patient is a mosaic XY/XX with ambiguous genitalia due to his classic 11-OHD or if the former are due to partial androgen resistance as seen in Reifenstein syndrome, or yet another etiology. Since biochemically our patient has classical 11-hydroxylase deficiency, it is not immediately apparent why his height (178 cm) was normal, as untreated patients generally have early epiphyseal closure and reduced adult height as a result of their hyperandrogenism. It is possible that if he has partial androgen resistance, his skeleton is also androgen resistant and thus, not susceptible to early epiphyseal closure. Growth is reported to be normal in XY children with androgen resistance and adult stature is reported to be normal for adult males and tall for adult females suggesting a putative Y-linked gene function which affects growth independently of testosterone [73].

Vitamin D repletion may result in dramatic and rapid biochemical improvement in classical 11-OHD patients who are also Vitamin D deficient.

The biochemical response seen is supportive of the concept that IR is pivotal in the expression of CAH and that treatments directed at IR may provide normalization of abnormal steroid metabolite levels without resulting in glucocorticoid side effects.

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