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

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).

Study Overview

• Status: Not yet recruiting
• Conditions: Disorder of Sex Development, 46,XY
• Intervention / Treatment: Drug: Testosterone gel; Drug: Placebo

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Anticipated): 1
• Phase: Phase 3

Contacts and Locations

Study Locations

• Netherlands
  • Zuid-Holland
    • Rotterdam, Zuid-Holland, Netherlands, 3015GD
      • Erasmus MC
      • Principal Investigator: Laura de Graaff, MD, PhD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 34 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Testosterone; Testosterone gel (20 mg/day) for 8 weeks per period.	Drug: Testosterone gel; The route of administration is transdermal.; Other Names: AndroGel
Placebo Comparator: Placebo; Placebo gel (20 mg/day) for 8 weeks per period.	Drug: Placebo; The route of administration is transdermal

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Fatigue (Checklist of Individual Strength)	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.	Baseline to 420 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Quality of Life (5-level EQ-5D)	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.	Baseline to 420 days
Laboratory levels	The following laboratory levels will be measured: Testosterone (nmol/L); Dehydroepiandorosterone (DHEA) (micromol/L); Estradiol (pg/mL); Hematocrit (%)	Baseline to 420 days
Bone density	Dual Energy X-ray Absorptiometry scan will be performed to measure bone density.	Baseline to 420 days
Goal attainment scaling	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.	Baseline to 420 days
Number of adverse events	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	Baseline to 450 days

Collaborators and Investigators

• Sponsor: Erasmus Medical Center

Study record dates

Study Major Dates

• Study Start (Anticipated): June 1, 2021
• Primary Completion (Anticipated): July 26, 2022
• Study Completion (Anticipated): July 26, 2022

Study Registration Dates

• First Submitted: March 26, 2021
• First Submitted That Met QC Criteria: April 2, 2021
• First Posted (Actual): April 5, 2021

Study Record Updates

• Last Update Posted (Actual): April 5, 2021
• Last Update Submitted That Met QC Criteria: April 2, 2021
• Last Verified: April 1, 2021

More Information

Terms related to this study

• Keywords: 17-beta-hydroxysteroid dehydrogenase type 3 deficiency
• Additional Relevant MeSH Terms: Endocrine System Diseases; Gonadal Disorders; Urogenital Abnormalities; Congenital Abnormalities; Disorders of Sex Development; Disorder of Sex Development, 46,XY; Physiological Effects of Drugs; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Androgens; Testosterone
• Other Study ID Numbers: N-of-1 DSD

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes
• IPD Plan Description: Individual participant data is available upon reasonable request.
• IPD Sharing Time Frame: The data will become available after completion of the study and only upon reasonable request and with permission of the participant.
• IPD Sharing Access Criteria: A motivated request.
• IPD Sharing Supporting Information Type: Study Protocol; Statistical Analysis Plan (SAP)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No