Hysterectomy in a phenotypic male with congenital adrenal hyperplasia (CAH)

Abstract

A young adult patient with 46XX congenital adrenal hyperplasia (CAH) presented with recurrent painful haematuria. CAH was diagnosed at birth following ambiguous genitalia. Hormonal treatment was started, female gender was assigned and feminising genitoplasty was planned, however the patient was lost to follow-up. Gender dysphoria started to occur during childhood which prompted the family to raise the patient as a boy. He eventually identified himself as a male. Examination revealed a male phenotype with severely virilised genitalia. Imaging studies confirmed the presence of uterus with low confluent urogenital sinus. Total abdominal hysterectomy with bilateral salpingo-oophorectomy was performed, and the troublesome symptoms were cured.

Background

Congenital adrenal hyperplasia (CAH) is a group of genetic disorders that arise from defective adrenal steroidogenesis involving three major pathways, that is, glucocorticoids, mineralocorticoids and sex steroids. Deficiency in the 21-hydroxylase enzyme is responsible for 95% of cases,¹ causing inadequate production of cortisol, aldosterone or both. As a result, accumulated hormone precursors to the enzymatic defect are shunted into the sex steroid pathway causing androgen excess. Androgen is the key hormone in the development of male sexual phenotype, behaviour, sexual orientation and gender identity.² In genotypic female XX CAH, androgen excess not only can cause masculinisation of the external genitals but also the brain and behaviour.³ This is the basis of gender dysphoria.

Classical CAH can be divided into the serious life-threatening ‘salt-losing form’ or the ‘simple-virilising form’. Most cases are diagnosed in the new-born and lifelong treatment is indicated to correct hormone deficiencies, prevent adrenal crisis and mitigate the androgen excess. Apart from hormonal treatment, early gender assignment with early corrective genitoplasty is necessary. In recent years, however, the management approach in CAH is to defer surgery until the patients themselves can become involved in the decision making.⁴

In contrast to the management of the disease in childhood, knowledge in the management of adult CAH is limited, especially in adult patients reared as male who default childhood treatment or who present late. We hereby illustrate the management of a severely virilised adult XX CAH with a focus on gynaecological surgery as a definitive treatment for the patient’s troublesome symptoms.

Case presentation

A young adult patient with underlying CAH presented with recurrent cyclical painful haematuria for the past few years. It is usually associated with lower abdominal pain that would occur for several days in a month. The pain is worse with passing out blood clots. Apart from pain and haematuria, he has no other complaints.

CAH was diagnosed following detection of ambiguous genitalia at birth. Chromosomal analysis showed 46 XX genotype female with absent SRY gene. Female gender was assigned, hormonal treatment was initiated, and the patient was scheduled for corrective feminising surgery; however, he was lost to follow-up due to sociofinancial issues.

The patient was raised as a girl until 7 years old. At 8 years old, he started behaving like a boy and refused to be dressed as a girl. He was most comfortable wearing boy’s clothes and interested in playing only with boys. He insisted on being called a boy’s name and he would throw tantrums if anyone addressed him as a girl. His family then changed his sex rearing. There was no past history of illness or hospital admission to suggest adrenal crisis. Recurrent painful haematuria started when he was 16 years old.

On examination, the patient has a male phenotype. His height was: 154 cm, and weight was 57 kg. He appeared tanned with absent facial hair. Axillary hair was sparse and breasts development was at Tanner stage 2. The pubic hair was at Tanner stage 4 with male pattern distribution. The abdomen was soft and non-tender, and no abdominal mass was palpable. Both labioscrotal sacs were empty and there was a marked clitoromegaly with phallus length about 7 cm with chordee. A single orifice on the urogenital region was seen at the base of the proximal phallus.

Investigations

Laboratory workup showed normal serum Follicle Stimulating Hormone (FSH), Luteinizing Hormone (LH), progesterone and estradiol (table 1). Raised serum 17-hydroxyprogesterone and low serum cortisol were consistent with the diagnosis of CAH. Other blood tests including the sodium, potassium and chloride levels were normal. Microscopic urine examination was also normal.

Table 1.

Blood hormonal profile

Blood test	Value	Reference values
FSH	4.95 IU/L	Male: 1.27–19.26 IU/L Female mid-follicular: 3.85–8.78, mid-cycle peak: 4.54–22.51, mid-luteal: 1.79–5.12 IU/L
LH	3.80 IU/L	Male: 1.24–8.62 IU/L Female: mid-follicular: 2.12–10.89, mid-cycle peak: 19.18–103.03, mid-luteal: 1.20–12.86 IU/L
Progesterone	15.57 nmol/L	Male: 0.45–6.55 Female mid-follicular: 0.99–4.83, mid-luteal: 16.41–59.02 nmol/L
Estradiol	116.4 pmol/L	Male: <172.5 pmol/L Female: mid-follicular: 99–631.5, mid-luteal: 179.9–1068.4, periovulatory: 348.8–1589.7
testosterone	6.17 nmol/L	6.07–27.08 nmol/L
17-hydroxyprogesterone	122.2 nmol/L	0.61–4.24 nmol/L
Cortisol	85 nmol/L	AM cortisol: 185–624 PM cortisol: <276

FSH, Follicle Stimulating Hormone; LH, Luteinizing Hormone.

Transabdominal ultrasound revealed presence of uterus with normal adnexae. Genitogram was unsuccessful due to pain following failure to cannulate the urogenital sinus orifice with a small paediatric Foleys catheter. MRI confirmed the presence of low confluent urogenital sinus and no adrenal tumour was visualised.

Differential diagnosis

Patients with CAH may experience pain for reasons either specific to the disease or not related to the disease. The most important differential diagnosis is Addisonian crisis. Even though the patient is a ‘simple viriliser’ and not a ‘salt waster’, adrenal crisis may still occur especially during acute stressful events. However, this diagnosis is less likely in this case as there were no other supporting clinical or laboratory features.

Enlarged adrenal gland in CAH as in cases of adrenal tumours like myelolipomas may also cause pain. Although the patient experienced some degree of lower abdominal pain associated with painful haematuria, pain from adrenal tumours are not typically cyclical or associated with bloody urine. In addition, diagnostic imaging modalities have ruled out this possibility.

Urinary tract calculi or urinary tract infection are two reasonable differential diagnoses in this case. The abnormality of lower urinary tract in the form of urogenital sinus may cause pooling of urine and predisposes this patient to higher risk of recurrent infection and calculi. Nevertheless, urine microscopic and ultrasound examination did not support either diagnosis.

In females, cyclical abdominal pain is usually related to menses. In many cases there are no underlying pathologies, but in some cases, dysmenorrhoea could be secondary to pathologies like endometriosis and pelvic inflammatory disease. In cases of urogenital sinus, obstruction to the menstrual flow may result in haematocolpos and cause cyclical pain. In this patient, however, findings from imaging studies did not suggest any of these diagnoses.

This patient has a female genotype with complete female internal organs including the uterus and ovaries. In addition, he also has a persistent urogenital sinus (PUGS) where there is a single common channel for both urinary and reproductive tracts. In view of the typical history of cyclical abdominal pain and haematuria, it is highly possible this patient has menses which is being passed out as haematuria. We believe the age of menarche was at 16 years old when he first manifested the symptoms. We also believe based on the failed cannulation during genitogram examination, cyclical abdominal pain most probably resulted from passing out menstrual blood and blood clots through the small opening of the urogenital sinus.

Treatment

Multidisciplinary team consisting of gynaecologists, endocrinologists, psychiatrists, psychologists and plastic surgeons comanaged the patient. He was treated with analgesics to relieve the pain. Physiological dose of glucocorticoid therapy was started. Multiple in-depth assessments were performed by the psychologists and psychiatrists to affirm his gender identity and to exclude neuropsychiatric disorders. His cognitive function was intact. There was no evidence suggestive of anxiety-depressive disorders. He identified himself as a man and wished to remain as a man. We proposed hysterectomy as the definitive treatment for his symptoms. Although he was initially upset with future fertility consequences following surgery, he finally came to term with this issue and consented for the operation.

Outcome and follow-up

Total abdominal hysterectomy with bilateral salpingo-oophorectomy was performed uneventfully under steroid cover. Postoperative recovery was uneventful and there were no subsequent episodes of painful haematuria. Testosterone replacement therapy was started after the operation. Gender affirming surgeries are planned in due time.

Discussion

Sharma and Gupta⁵ studied seven XX CAH out of total 173 CAH patients at their centre, who presented late and reared as males. Only one patient in their cohort was diagnosed early but defaulted follow-up, as in our case. Limited parental understanding of the condition, non-adherence to treatment,⁶ general male behaviour of the patient, socioeconomic compulsion⁵ and financial constraint⁷ are among the reasons identified contributing to late presentation. Limited access to medical care because of war was also cited to be the cause.⁸

Presenting complaints were mainly developmental anomalies of sexual organs including hypospadias, well developed phallus, chordee, cryptorchidism and gynaecomastia.⁵ Haematuria occurs in some patients which is typically recurrent or cyclical^{5 9} and can be associated with pain.⁹ Recurrent painful haematuria was the main complaint in our case. Haematuria originates from the menstrual blood which passes out through a single common channel for both urethra and vagina in cases of PUGS. In fact, CAH is the most common cause of PUGS. Pain could be caused by passage of blood clots through the small opening of PUGS⁹ as illustrated in our case. Haematocolpos was also reported to be the cause of recurrent abdominal pain in CAH patients.⁷

Our patient was assigned a female gender at birth but self-identified a male gender since 8 years old. He came to medical attention after having established male gender identity for more than 10 years. This is not surprising since he was exposed to a long period of high androgen. Androgen plays an important role in the development of male sexual phenotype, sexual orientation, behaviour and gender identity.² Increase in androgen not only can change the external genitalia but also can change the sexual behaviour. Previous reports confirmed that patients with virilising CAH with late presentation almost always prefer male gender.^{2 8–11}

Gender dysphoria is an important aspect of management to be looked into especially in severely virilised CAH. Gender dysphoria is defined as clinically significant distress resulting from an incongruence between the experienced gender and the gender assigned at birth.¹² If CAH is diagnosed early in infancy and treated with glucocorticoids, a large majority of female raised patients will develop female gender identity and not gender dysphoric.¹³ On the other hand, Dessens et al¹⁴ reported up to 12.1% of their male raised patients experienced serious gender identity problems. Literature review in 2010, however, suggested that gender dysphoria is uncommon among highly virilised 46 XX patients who are reared as males.¹⁵ Our patient was gender dysphoric during childhood, therefore his family raised him as a boy since he was 8 years old. He has since identified himself as being a male, mentally and psychologically, and he is comfortable with his current gender with no evidence of distress.

During surgery, the uterus, ovaries and fallopian tubes are removed as well as part of the vagina through a low transverse abdominal incision. The lower vagina which invariably communicated with the ‘male’ urethra was preserved. The risk of injury to the urinary system is less in cases of low confluence PUGS compared with high confluence PUGS. Subsequent excision of the vaginal remnant may only be necessary if there is a complicating urinary tract infection or other problems in the follow-up.¹⁶ Interestingly, laparoscopic subtotal hysterectomy with preservation of uterine cervix has been described in an 11-year-old child with CAH.¹⁷ The author felt that laparoscopy should be the operation of choice given the advantages of laparoscopy over laparotomy in terms of convalescence and cosmetics.¹⁷ It is interesting to also note that a case of cervical cancer has in fact been reported in a 78-year-old phenotypic male CAH.¹⁸ Total laparoscopic hysterectomy, however, would not be technically feasible in cases of CAH with PUGS due to their unique genital anatomy.

Gender affirming surgery is the next important step in the management of our patient. Male staged urethroplasty, correction of chordee and insertion of testicular implants would strongly affirm the male gender. This is done with the intention to allow patients to fit better in society and for them to be able to pursue mature heterosexual relationships later.

Patient’s perspective (translated from Bahasa Malaysia).

I knew for a very long time that I was different from my other friends. I was actually born as a girl and over the years, because of the medical problem that I have, I became a man. I was told that I have an excessive amount of male sex hormones due to deficiency of another hormone in my body. To treat my condition, doctors started treatment since I was a baby but my family stopped bringing me to the hospital after some time. Hospital visits became too expensive for us especially after the death of my father. Despite not being on treatment, I have always been a healthy person.

I could still remember my early childhood. I had a girl’s name and I wore dresses. I even remember my mother tying and pleating my long hair. According to my mother, when I was around 8 years old, I started to refuse wearing girl’s clothes, wanted to play with boys only and insisted on being called a boy’s name. As I grew older, I made many male friends and some really close female friends. Some of my friends knew about my past history but it was never a big deal to them.

Few years ago when I started to have blood in my urine. It would occur for several days in a month. Mostly it was painless and did not disturb me so much but sometimes I would experience severe excruciating pain whenever I passed out blood clots. I usually took painkillers and I would be okay afterwards but lately the pain had gotten worse. I decided to see a doctor in the community clinic who then referred me to the hospital.

I was seen by many doctors from different specialities in the hospital. They explained to me that the blood in my urine was actually my periods coming from the uterus since genetically I am a female. I was a little surprised when they told me that. Many treatment options were discussed with me. I was also asked by the attending doctors whether I want to continue being a man or otherwise. Hysterectomy was suggested as the definitive treatment for my symptoms. At first, I was very sceptical and I had a lot of doubts. I wanted the pain to go away permanently but without the uterus I would never be able to father my own children.

Surely having kids was an important issue to me, but the question is at what price? Now I live and breathe as a man. Would I want to change my gender? In any case, I was given a lot of time and space for me to think. The doctors answered many of my questions and I sought opinions from my family and friends. Everybody was very supportive. The subsequent episode of pain helped me to make a decision. I finally decided to remove my uterus.

Few months ago, I underwent surgery to remove my uterus and ovaries. Far from having any regrets, I have to say that I was really glad with my decision. The pain has totally disappeared and I have no more blood in my urine. Now, I look forward to the upcoming corrective surgery.

Learning points.

• Patients with congenital adrenal hyperplasia(CAH) with XX female genotype who default treatment and follow-up may be severely virilised and reared as males.

• These patients may turn up for medical attention in later life with sexual developmental anomalies or with troublesome symptoms.

• Recurrent cyclical haematuria could be the presenting complaint when there is a single outflow channel in cases of CAH with concurrent persistent urogenital sinus, and this symptom could be associated with pain.

• Hysterectomy to manage troublesome painful haematuria in a virilised CAH patient is a valid management option in cases when the sex allocation is male.

Ethics statements

Patient consent for publication

Consent obtained directly from patient(s)