CASE 9 – A CASE OF PRIMARY AMENORRHEA

Original case Carla Costa et al

A 15-year-old adolescent was raised according to female gender. The patient had no significant past medical or surgical history. The family history was negative, non-consanguineous parents. At puberty the adolescent had primary amenorrhea and a severe virilization with deep voice, masculine muscular development, increased growth of body, and facial hair.

Q Define primary amenorrhea ?

Absence of menarche by age 15 years in presence of secondary sexual characteristics or absence of menarche by age 13 in absence of secondary sexual characteristics.

Q Enlist the causes of Primary Amenorrhea

  1. Hypothalamic or Pituitary causes
    1. Functional Hypothalamic amenorrhea
    2. Hypogonadotropic hypogonadism
    3. Constitutional delay in puberty
    4. Sellar or Suprasellar tumors
    5. Pituitary irradiation
    6. Pituitary surgery
  2. Ovarian etiologies
    1. Gonadal dysgenesis
    2. Turner’s syndrome
    3. PCOS
  3. Defect in reproductive tracts
    1. Mullerian agenesis
    2. Imperforate hymen
    3. Vaginal agenesis
    4. Transverse vaginal septum
  4. Receptor abnormalities
    1. Complete androgen insensitivity syndrome
    2. Partial androgen insensitivity syndrome
  5. Enzyme abnormalities
    1. 5 alpha reductase deficiency
    2. 17 beta hydroxylase 3deficiency

Q From the history what is your diagnosis ?

We could think of two possibilities

  1. 5 alpha reductase deficiency
  2. 17 beta HSD 3 deficiency
  3. Partial androgen insensitivity syndrome

The physical examination showed a male phenotype with micropenis and blind vagina. Her breasts were Tanner stage 1, pubic and axillary hair was Tanner stage 4 with nonpalpable gonads (Fig. 1).

Q What is the meaning of this Tanner staging ?

  1. Breast are Tanner Stage 1 meaning no glandular tissue
  2. Pubic hair are Tanner stage 4 meaning they are adult like but sparing the medial aspect of thigh
  3. Axillary hair are tanner stage 4 meaning there is presence of axillary hair

Q What is the Prader Staging of the external genital organs ?

Prader Stage 3-4

Q What is the diagnosis after Physical examination ?

The same clinical suspicion at end of physical examination still remains.  However Partial androgen insensitivity syndrome may be ruled out because the child does not have gynecomastia and Tanner staging is 1. In  PAIS , the child would have additionally developed gynecomastia.

Q What investigations would you order ?

  1. Karyotype
  2. Serum testosterone
  3. Serum Dihydrotestosterone
  4. Serum FSH and LH
  5. Ultrasound of pelvis to look for Uterus
  6. Ultrasound or MRI abdomen to look for abdominal testis

The karyotype revealed 46,XY. An endocrinology study is show in Table 1,

Q What is your interpretation from the Endocrine lab tests ?

  1. My most likely diagnosis would have been 5 alpha reductase 2 deficiency. In this case the Testosterone would have been high while DHT would have been low with T/DHT ratio of >20. In this case both T and DHT are low normal with ratio of 18.
  2. My second differential is 17 beta HSD 3 deficiency in which case the Testosterone would be low while Androstenedione would be elevated which is seen in this case. The raised LH also goes in favour of this diagnosis. The T/A ratio at baseline in most of this cases is <0.8-1.0 and further reduces with HCG stimulation. This is an important test which firmly differentiates it from androgen insensitivity

Q What is your Final diagnosis ?

We are dealing with 17 beta HSD 3 deficiency.

Magnetic resonance imaging of abdominal–pelvic showed the presence of testicles in inguinal canal, seminal vesicle, prostate, and micropenis and the absence of uterus and vagina.

Q What would be the treatment in this case ?

  1. The most important aspect of treating this patient would be gender assignment.
  2. If such children are diagnosed in early childhood or infancy then they are generally reared as males. However if diagnosed later as in this case, the gender assignment is more complicated.
  3. The child should first undergo psychological counselling to confirm female gender identity.
  4. If the female gender identity is confirm then the child should undergo gonadectomy with correction surgery for external genitalia and should be started on estrogen replacement.
  5. If the child is raised as a male then surgery should be performed for the cryptochoidism and correction of the external genitalia. The child can then be supplemented with testosterone.

Treatment with gonadotrophin-releasing hormone (GnRH) analog and flutamide was started in the first year, with good results. The genetic study confirmed the mutation p.Glu215Asp on gene HSD17B3 in homozygosity.

Q What would be the role of this therapy in the present case ?

Flutamide is an antiandrogen. This therapy would halt the pubertal surge of androgens. This would buy time for further management.

The decisions about the management of the present case were made after interviews with the adolescent and her parents and in consultations among the endocrinologist, the surgeon, and the psychiatrist. During all procedures, the patient was accompanied by a child psychiatrist/psychologist.

The clinical course, the hormonal profile, and the karyotype (46,XY) were compatible with the diagnosis of 17β HSD3 deficiency, which was confirmed by DNA analysis. Upon discussing the possibilities for gender assignment, the father and the adolescent strongly opposed gender reassignment, expressing considerable fear of the social repercussions, especially considering the fact that they were members of a very small community. The teenager showed the desire to continue being a female, because she identified herself as a female. The pediatric surgeon explained all the procedures and the fact that if she wants to continue as a female it would eliminate the possibility of fertility. At the age of 16 years, gonadectomy was performed along with the surgical procedures to change external genitalia (Fig. 2). At this time, the patient stopped treatment with GNRH analog and flutamide and started to undergo estrogen replacement therapy. The microscopical examination of the testes showed normal testicular histology. No genetic analysis was made in the removed gonads.

After surgery and estrogen therapy she returned for a follow-up visit in a pleasant mood, more talkative, and dressed in very feminine clothes. She had breasts development under estrogen therapy. She did not express any regret about the surgical intervention, reported that her mood is consistently good and that socialization had significantly improved. She was no longer stigmatized, which is traumatic for DSD people.

 

Learning Points from this case

  1. Testosterone/ Androstenedione ratio of <0.8-1.0 generally helps in diagnosis of 17 beta HSD 3
  2. Gender assignment in 17 beta HSD3 is complex and when presenting at later age the importance to the psychological gender identity .
  3. Gynecomastia is a feature of Partial androgen insensitivity syndrome which is absent in 5 alpha reductase 2 and 17 beta HSD 3 deficiencies.

 

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