Positive fertility outcomes in a female with classic congenital adrenal hyperplasia following bilateral adrenalectomy
Our case highlights the disease related morbidities and significant challenges of managing adult females with classic CAH. Our patient’s weight loss, lack of adrenal crisis and improved quality-of-life 7 years after surgery supports adrenalectomy as a therapeutic option in select cases, and especially in the treatment of female infertility. Suboptimal response to medical management of her CAH and a strong desire for fertility led to the consideration of surgery.
Our patient suffered from a combination of glucocorticoid excess and hyperandrogenism during adolescence. Her course was complicated by poor compliance, a common occurrence in adolescents with a chronic condition requiring daily medication [8, 9]. Management of adolescents with classic CAH is particularly challenging and focuses on control of androgen excess while avoiding cushingoid side effects of overtreatment. Prevention of long-term adverse outcomes, such as suboptimal sexual health, infertility and tumor formation, is of utmost importance [8]. Adrenal hyperplasia, nodularity and tumor formation occur with long-standing poorly controlled disease and if not prevented can complicate disease management, as seen with our patient presented here.
The desire to avoid high dose glucocorticoids in order to achieve adrenal androgen suppression led to our use of the anti-androgen flutamide and a combined oral contraceptive pill. The use of this therapeutic approach to control the signs and symptoms of hyperandrogenism was successful, but the long-term success of this therapy is unknown because our patient eventually desired fertility. To address the androgen excess feature of CAH, peripheral blockade of androgens and androgen synthesis inhibitors have been used in clinical trials in prepubertal children with classic CAH and in a phase 1 study of adult women with classic CAH respectively, but this approach is not considered standard therapy [10, 11]. However, the use of an oral contraceptive and the antiandrogen spironolactone is commonly used in the treatment of non-classic CAH, the mild form of the disease [12]. We did not use spironolactone in this patient with classic CAH due to the diuretic effect of spironolactone and because it is a weaker anti-androgen than flutamide. Flutamide acts to inhibit androgen activity and oral contraceptives are protective of the ovaries from becoming polycystic and androgen secreting. A study of flutamide administration in 8 patients with polycystic ovary syndrome showed an improvement in hirsutism, a decrease in androgen levels and a reduction in ovarian volume possibly due to flutamide’s effects on androgen biosynthesis in ovarian theca cells [13].
Adrenalectomy has been considered as a prophylactic treatment option for classic CAH [7, 14], but our case does not support this approach. A long term study of a 3 year old with SW CAH due to a double null mutation in CYP21A2 who underwent prophylactic adrenalectomy revealed normal growth and development due to management with lower dose glucocorticoid replacement post adrenalectomy [15]. But caution should be used because genotype does not always predict adult phenotype [16]. Patients with salt-wasting CAH may do well as adults, while patients with simple virilizing CAH, such as the patient described here, may suffer from multiple co-morbidities. The distinction between SW and SV, although sometimes useful in the management of young children, may be unimportant in the management of adults with classic CAH [17]. Our patient is an example of this phenomenon. The factors that contribute to the development of adult co-morbidities require further study.
A common concern regarding adrenalectomy in patients with CAH is not the surgical procedure itself but the long-term risks following removal of the adrenals. Most important is the concern regarding the mortality risk and the potential protective function of the adrenals in CAH, which when stressed may produce small amounts of cortisol. There is also an observed decrease in blood pressure after adrenalectomy which may reflect a loss of mineralocorticoid protective effects against volume depletion [17]. In SW CAH, the adrenal glands are unable to produce sufficient amounts of cortisol and epinephrine and thus surgical removal of the adrenal glands most likely does not increase the risk of an adrenal crisis [18]. However, our patient had SV CAH and therefore would be expected to have some endogenous cortisol and epinephrine secretion. Indeed, her adrenal glands, despite generalized hypertrophy, maintained zonation with a small area of distinct medulla. Despite having a less severe genetic mutation and less developmental impairment of the adrenal gland, several years of noncompliance induced adrenal hypertrophy leading to a state of excess adrenal androgen production which was difficult to control with medical management alone.
The outcome after surgery with respect to quality-of-life, disease control and fertility indicates that bilateral adrenalectomy was a positive therapeutic option for our patient. Similarly, Ogilvie et al. reported two females with classic CAH who underwent adrenalectomy for infertility and became pregnant within 2 years [19].
Our patient continues on hydrocortisone and fludrocortisone replacement and is being followed annually. Given that our patient is doing well on glucocorticoid and mineralocorticoid replacement, we have not considered dehydroepiandrosterone (DHEA) supplementation, which would only be considered if she were to develop low libido, depressive symptoms or low energy despite optimized glucocorticoid and mineralocorticoid replacement [20]. In addition to monitoring glucocorticoid replacement based on clinical assessment, management includes measuring 17-OHP and androstenedione levels for evidence of adrenal rest tissue and measurement of plasma renin activity to assess mineralocorticoid replacement. A review of 18 cases of patient with CAH who had undergone adrenalectomy revealed that approximately one-third of patients had evidence of adrenal rest tissue activation following adrenalectomy leading to increased dosing of glucocorticoid replacement [7]. As suggested in the recent Endocrine Society Clinical Practice Guideline for management of primary adrenal insufficiency, measurement of ACTH to guide glucocorticoid replacement is not recommended [20].
Many patients who might be considered for adrenalectomy due to uncontrolled hyperandrogenism have a history of noncompliance, as seen in our patient. This habit of non-compliance must be carefully addressed prior to surgery and monitored after surgery because of the risk of experiencing a life-threatening adrenal crisis. Informed consent and patient education with a discussion of potential risks is essential. Close monitoring is warranted.