From hirsutism and menstrual issues to congenital adrenal hyperplasia: is genetic testing a stepping stone for 3-beta-hydroxysteroid dehydrogenase type 2 deficiency?

1. Introduction

Hirsutism and menstrual cycle anomalies represent a multidisciplinary panel of clinical, laboratory and imaging findings that might impair the overall quality of life, the reproductive potential, and even bring different comorbidities such as metabolic issues that require an additional (specific) intervention^(1,2).

The most common cause of hirsutism is idiopathic, while the most frequent condition involving both mentioned clinical elements is polycystic ovary syndrome (PCOS). Among the rarest causes, there are the adrenal tumors, particularly adrenocortical carcinoma, respectively, ovarian neoplasia with endocrine activity, namely over-production of androgens. Metabolic syndrome and extreme nutritional impairment, apart from accompanying PCOS, might bring some anomalies in the field of gynecological endocrinology, as well^(3,4). Other menstrual disturbances and infertility (not related to hirsutism) involve thyroid panel, mostly autoimmune thyroid diseases, syndromic or not^(5-8).

Congenital adrenal hyperplasia (CAH) represents another challenging topic that, in cases with late onset and mild phenotypes which are not early detected as newborn or during childhood, may overlap with the aforementioned picture of PCOS. Its diagnosis in these particular cases is very difficult; the genetic testing, if suspected, is not available in many centers or it represents a potential source of bias, thus the management is mainly based on the clinical and laboratory findings, rather than having a prompt genetic confirmation (which, anyway, should be very helpful for the global case strategy and management)^(9,10).

In this paper, our purpose is to present an atypical case of CAH that displayed PCOS features for a long time and associated some pitfalls at the genetic testing.

2. Case presentation

A 26-year-old female presented for hirsutism and amenorrhea. The patient was suffering from excessive hair growth since childhood, and she had developed hirsutism during adolescence. She experienced menarche at 13 years of age and had an irregular menstrual cycle all throughout adolescence. At the age of 16 years old, the patient received treatment with dydrogesterone and metformin due to amenorrhea associated with weight gain of 15 kg in three months.

However, her menstrual cycle remained irregular. At the age of 24 years old, she started the treatment with oral contraceptives (ethinylestradiol/chlormadinone acetate), and the menstrual cycle became regular. During this time, the patient also completed 11 successful sessions of laser hair removal, leading to the remission of hirsutism. After two years of treatment, following oral contraceptive cessation, hirsutism and amenorrhea relapsed. The patient was referred for further evaluation of this medical history. 

On current admission, the physical examination revealed hirsutism, with a Ferriman-Gallway score of 32, and a lower height than the target (patient’s height of 162 cm, mid-parental height of 169 cm). The patient had normal disposition of adipose tissue, with a normal Body Mass Index of 22.48 kg/m².

Further on, biochemical tests suggested insulin resistance, with a HOMA-IR of 3 (fasting glucose of 95 mg/dL, normal: 70-100 mg/dL, and serum insulin of 12.62 µg/mL, normal: 2.6-24.9 µg/mL), but the oral glucose tolerance test did not confirm any impaired glucose tolerance (Table 1).
 

Cushing’s syndrome was excluded through additional dynamic hormonal tests in terms of oral dexamethasone suppression test (Table 2).
 

The hormonal panel showed increased levels of dehydroepiandrosterone sulfate (DHEA-S), androstenedione, 17-hydroxyprogesterone, testosterone and luteinizing hormone (LH), with an LH to FSH (follicle-stimulating hormone) ratio of 5.3 (Table 3).
 

Moreover, the androstenedione to testosterone ratio was over 8.33. A long dexamethasone 2 mg/day x 4 days test revealed an 82% suppression of DHEA-S and 48.5% suppression of 17-hydroxyprogesterone (Table 4).
 

The ACTH stimulation test, using Synacthen® 250 µg intravenously, was performed, and it excluded 21-hydroxilase deficiency (this being the most frequent form of CAH) – Table 5.
 

A transvaginal ultrasound found polycystic ovaries, while the abdominal computed tomography revealed bilateral adrenal hyperplasia (Figure 1 A, B).
 

Based on these clinical and laboratory findings, a non-classic form of CAH by 3-beta-hydroxysteroid dehydrogenase type 2 deficiency (HSD3B2) was considered, thus genetic testing was recommended. Bidirectional sequence analysis of the entire coding region and splicing sites of the HSD3B2 gene did not reveal a specific pathogenic variant.  The patient was prescribed oral contraceptives (ethinylestradiol/chlormadinone acetate) and 50 mg of spironolactone daily, along with periodic checkup. Nevertheless, CAH diagnosis is still sustained, and a secondary genetic testing in a high-volume center is planned.

3. Discussion

In our patient’s case, the clinical picture of hirsutism resistant to laser removal, along with chronic anovulation, as well as the patient’s insulin resistance required a differential diagnosis between CAH and PCOS. CAH is the second most frequent diagnosis in females with hirsutism and amenorrhea, accounting for up to 14% of cases, surpassed only by PCOS⁽¹¹⁾. Non-classic forms of CAH may have mild clinical presentations closely resembling PCOS, with androgen excess, hirsutism, anovulation and even polycystic ovaries at ultrasound and insulin resistance as metabolic elements^(12-14).

One of the rarest enzymatic defects leading to CAH is 3bHSD2 deficiency. The non-classic form of 3bHSD2 deficiency is still controversial, with genetic evidence unable to identify mutations in many patients with biochemical anomalies and lack of clinical improvement following glucocorticoid treatment⁽¹⁵⁾. On the other hand, increased corticoids exposure should be carefully assessed in order to avoid unnecessary side effects of glucocorticoids in cardiovascular and glucose profile, as well as bone health⁽¹⁶⁾.

An increase in 17-hydroxipregnenolone and elevated ratios of ∆5-steroids (17-hydroxipregnenolone, DHEA-S) to ∆4-steroids (17-hydroxiprogesterone, androstenedione) are the biochemical clues in selecting candidates for genetic testing^(15,17).

In our patient’s case, biochemically, a high LH to FSH ratio pleaded for PCOS. However, an elevated 17-hydroxiprogesterone level and adrenal hyperplasia found on computed tomography prompted further investigations for CAH. After having excluded, through biochemical testing, other causes of adrenal hyperplasia such as ACTH dependent or ACTH independent conditions (endogenous Cushing’s syndrome) and given that there were no indications of other etiologies such as infectious processes or lipomatous metaplasia, CAH was taken into consideration as the underlying cause of these imagistic findings and clinical anomalies⁽¹⁸⁾.

Even though PCR (polymerase chain reaction) followed by sequence analysis should be able to identify most common mutations, this method may still miss rare mutations. Thus, a negative genetic testing result may not always rule out the diagnosis⁽¹⁹⁾. Treatment options for hyperandrogenism are similar for both PCOS and non-classic CAH, and they include oral contraceptives, spironolactone and cosmetic treatments such as laser, as applied in this case. However, differentiating between CAH and PCOS is crucial, considering the impact on the possible offspring and the possible need of glucocorticoid treatment^(20,21). Moreover, in rare cases, the patients with CAH may develop adrenal tumors, requiring close monitoring and even adrenalectomy in a selected subgroup of individuals, a scenario that is not registered in PCOS⁽²²⁾.

4. Conclusions

One of the rarest enzymatic defects leading to CAH is 3bHSD2 deficiency. The non-classic form of 3bHSD2 deficiency is still controversial, with genetic evidence unable to identify mutations in many patients with biochemical anomalies and the lack of clinical improvement following glucocorticoid treatment. The improvement of genetic testing techniques and further research prompt a better understanding of steroidogenesis defects.  

Abbreviations: ACTH = adrenocorticotropic hormone; 3βHSD2 = 3-beta-hydroxisteroid dehydrogenase type 2; CAH = congenital adrenal hyperplasia; DHEA-S = dehydroepiandrosterone sulfate; FSH = follicle-stimulating hormone; LH = luteinizing hormone; PCOS = polycystic ovary syndrome; PCR = polymerase chain reaction.

Corresponding author: Ana-Maria Gheorghe, e-mail: anamaria.gheorghe96@yahoo.com

CONFLICT OF INTEREST: none declared.

FINANCIAL SUPPORT: none declared.

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