Testosterone Treatment in a Patient With 17β-hydroxysteroid Dehydrogenase Type 3 Deficiency: an N-of-1 Study (N-of-1 DSD)

Testosterone Treatment in a Patient With 17β-hydroxysteroid Dehydrogenase Type 3 Deficiency: an N-of-1 Study

Testosterone Treatment in a Patient With 17β-hydroxysteroid Dehydrogenase Type 3 Deficiency: an N-of-1 Study

A 38-year old women with a 46,XY disorder of sex development (DSD) based on a 17β-hydroxysteroid dehydrogenase type 3 deficiency (17β-HSD3) was seen at the department of Internal Medicine-Endocrinology at the Erasmus MC, Rotterdam, the Netherlands. The patient presented with fatigue, concentration problems and feelings of restlessness. In the past, the patient had undergone a gonadectomy at 9 months of age. In a follow-up visit at the outpatient clinic, the patient mentioned that friends with DSD had successfully been treated with testosterone and the patient requested testosterone treatment for her complaints. In the literature, nothing is known about the usefulness of testosterone treatment for women with 17β-HSD3. For other forms of 46,XY DSD like complete androgen insensitivity syndrome (CAIS), limited data are available about testosterone treatment. Two studies have compared the effects of estrogen and testosterone replacement therapy on psychological wellbeing, quality of life (QoL) and sexual function in women with CAIS. The results were not conclusive, as one of them found a positive effect of testosterone replacement therapy on sexual function compared to estrogen, whereas the other study found no differences. In order to evaluate the effect of testosterone treatment independent of a possible placebo effect, the usefulness of testosterone treatment in this individual patient with 17β-HSD3 will be investigated in an N-of-1 trial in order to improve the clinical care for this patient. The primary objective is to determine the efficacy of testosterone treatment for fatigue on an individual level in a patient with 17β-HSD3 as assessed with the Checklist Individual Strength (CIS-20).

A 38-year old women with a 46,XY disorder of sex development (DSD) based on a 17β-hydroxysteroid dehydrogenase type 3 deficiency (17β-HSD3) was seen at the department of Internal Medicine-Endocrinology at the Erasmus MC, Rotterdam, the Netherlands. 17β-HSD3 is a rare disorder characterized by a (despite the presence of a Y chromosome) female habitus in almost all newborns, with congenital agenesis of the uterus and ovaries. During puberty, patients with 17β-HSD3 often develop secondary male characteristics, such as deepening of the voice, male pattern body hair, and clitoromegaly. The patient presented with fatigue, concentration problems and feelings of restlessness. In the past, the patient had undergone a gonadectomy at 9 months of age. In a follow-up visit at the outpatient clinic, the patient mentioned that friends with DSD had successfully been treated with testosterone and the patient requested testosterone treatment for her complaints. The patient was aware of the fact that the positive effect noticed by the patients' friends could be (partly) explained by placebo effect. In the literature, nothing is known about the usefulness of testosterone treatment for women with 17β-HSD3. For other forms of 46,XY DSD like complete androgen insensitivity syndrome (CAIS), limited data are available about testosterone treatment. Two studies have compared the effects of estrogen and testosterone replacement therapy on psychological wellbeing, quality of life (QoL) and sexual function in women with CAIS. The results were not conclusive, as one of them found a positive effect of testosterone replacement therapy on sexual function compared to estrogen, whereas the other study found no differences. In order to evaluate the effect of testosterone treatment independent of a possible placebo effect, the usefulness of testosterone treatment in this individual patient with 17β-HSD3 will be investigated in an N-of-1 trial in order to improve the clinical care for this patient. The primary objective is to determine the efficacy of testosterone treatment for fatigue on an individual level in a patient with 17β-HSD3 as assessed with the Checklist Individual Strength (CIS-20). Secondary objectives are to determine the effect of testosterone treatment on the QoL (5-level EQ-5D), testosterone, dehydroepiandorosterone (DHEA), and estradiol levels, on bone density, and on specific personalized goals that are important to the patient and her environment (Goal Attainment Scaling). To monitor the safety of testosterone treatment, hematocrit levels will be measured and the occurrence of adverse events will be evaluated.

N-of-1 study: cross-over study in 1 patient with 2 cycles that each consists of 2 periods (one period of placebo and one period of active treatment).

The participant and investigator are blinded. The investigator is also the care provider and investigator.

Fatigue is measured with the Checklist of Individual Strength (CIS-20). The CIS-20 consists of 20 questions. The score ranges from 20 - 140. A score of 27-35 means increased fatigue. A score >35 means extreme fatigue.

Quality of life is measured with the 5-level EQ-5D (EQ-5D-L5). The range of the EQ-5D-5L is from 0 to 100. A higher score means a better outcome.

The following laboratory levels will be measured: Testosterone (nmol/L) Dehydroepiandorosterone (DHEA) (micromol/L) Estradiol (pg/mL) Hematocrit (%)

GAS is an individualized outcome measure in which several personal goals and the corresponding scaling are defined in consultation with the patient. The scaling is standardized, which makes it possible to reliably measure the change in the situation of the patient. The levels range from -3 to +2. A higher level means a better outcome. The predefined personal goals are a measure of the effectivity of the treatment. If possible, three goals will be set.

All adverse events that occur from start of treatment until 30 days after last administration will be described to assess the safety of testosterone treatment. Adverse events are defined as any undesirable experience occurring during the study, whether or not considered related to testosterone treatment

Inclusion Criteria: - N/A Exclusion Criteria: - N/A The study is especially designed for a specific female patient. The patient is 38 years old at the moment. Since the study is especially designed for this patient, there are no formal inclusion and exclusion criteria.

The data will become available after completion of the study and only upon reasonable request and with permission of the participant.