3β-hydroxyandrost-5-en-17-one acetate

Exposure related observations in humans: other data

Administrative data

Endpoint:

exposure-related observations in humans: other data

Type of information:

experimental study

Adequacy of study:

other information

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Data source

Reference

Reference Type:

publication

Title:

Oral Dehydroepiandrosterone for Adrenal Androgen Replacement: Pharmacokinetics and Peripheral Conversion to Androgens and Estrogens in Young Healthy Females after Dexamethasone Suppression

Author:

ARLT W, JUSTL H-G, CALLIES F, REINCKE M, HUBLER D, OETTEL M, ERNST M, SCHULTE HM, and ALLOLIO B

Year:

1998

Bibliographic source:

J Clinical Endocrinol Metab

Materials and methods

Endpoint addressed:

other: Dehydroepiandrosterone pharmacokinetics and conversion to androgens and estrogens in young healthy females

Principles of method if other than guideline:

The primary goal of this study was to define the optimum dehydroepiandrosterone (DHEA) dose necessary to restore hormone concentrations in DHEA-deficient women to the normal range. The study investigated the pharmacokinetics and biotransformation of orally administered DHEA in nine young, healthy female volunteers (age 19-30 years) after transient suppression of adrenal steroid synthesis by dexamethasone (4 x 0.5 mg/day for 4 days) and compared the results with baseline hormone secretion in these women. Diurnal blood sampling was performed during the early follicular phase of four subsequent menstrual cycles in a randomized cross-over design. Cycle 1 served as baseline. Preceding the study days during the cycles 2-4, all subjects were pretreated with oral dexamethasone for 4 days. On the study days 2-4, either placebo or 50 or 100 mg DHEA were administered orally at 0900 hours in a randomized order. On all four study days, 24-hour frequent blood sampling was performed. Mean serum concentrations of the following hormones were measured: Cortisol (nmol/L), DHEA (nmol/L), DHEA-sulfate (umol/L), Androstenedione (nmol/L), 5-alpha-androstane-3-alpha,17-beta-diol-17-glucuronide (nmol/L), Testosterone (nmol/L), Dihydrotestosterone (nmol/L), Estrone (pmol/L) and Estriol (pmol/L).

GLP compliance:

no

Remarks:

GLP compliance is not applicable to a human pharmacokinetics study.

Test material

Test material information

Constituent 1

Reference substance name:

Prasterone

EC Number:

200-175-5

EC Name:

Prasterone

Cas Number:

53-43-0

Molecular formula:

C19H28O2

IUPAC Name:

(3S,8R,9S,10R,13S,14S)-3-hydroxy-10,13-dimethyl-1,2,3,4,7,8,9,11,12,14,15,16-dodecahydrocyclopenta[a]phenanthren-17-one

Test material form:

solid

Details on test material:

white solid

Specific details on test material used for the study:

SOURCE OF TEST MATERIAL (Dehydroepiandrosterone; DHEA)
- Source: Jenapharm (Jena, Germany)
- Purity: Not specified

STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of the test material: Not specified
- Solubility and stability of the test substance in the solvent/vehicle: Not applicable

FORM AS APPLIED IN TEST
- 50 mg capsules (mean DHEA content of the capsules was 49.3 +/- 0.20 mg as determined by high performance liquid chromatography (HPLC)

Method

Ethical approval:

confirmed and informed consent free of coercion received

Remarks:

Before the study, the protocol had been approved by the Ethics Committee of the University of Wuerzburg and written informed consent was obtained from all volunteers.

Details on study design:

DETAILS ON HUMAN VOLUNTEERS
- Sex: Female
- No. of Volunteers: Nine
- Age: 19-30 years, mean age 23.3 +/- 4.1 years
- Smoking Status: Eight nonsmoking, one smoking
- Body Mass Index (BMI): 19.5 to 25.1 kg/m2 (mean 22.5 +/- 1.8 kg/m2)
- Hormonal Status: All volunteers were regularly menstruating and had normal baseline serum concentrations of dehydroepiandrosterone-sulfate, androstenedione and testosterone.
- Health Status: All volunteers had normal blood cell counts and normal hepatic and renal function parameters.

DETAILS ON STUDY PROTOCOL
- Study Design: Single-dose, randomized, cross-over design. Nine volunteers were studied during the early follicular phase off four subsequent menstrual cycles. Cycle 1 served as baseline. During cycles 2-4, all subjects were pretreated with oral dexamethasone (4 x 0.5 mg daily for 4 days) to suppress adrenal steroid synthesis. On the study days 2-4, either placebo or 50 or 100 mg DHEA were administered orally at 0900 hours in a randomized order.
- Blood Sampling: On all four study days, 24-hour blood sampling was performed, starting after an overnight fast at 0830 hours and ending at 0900 hours the following day [-30 (0830 hours), 0, 30, 60, 90, 120, and 150 minutes, and 3, 4, 5, 6, 7, 8, 10, 12, and 24 hours].
- Meals: Standardized meals were served at 1030, 1500, and 2100 hours.


DETAILS ON HORMONE ASSAYS
- Hormones Measured: Cortisol (nmol/L), DHEA (nmol/L), DHEA-sulfate (umol/L), Androstenedione (nmol/L), 5-alpha-androstane-3-alpha,17-beta-diol-17-glucuronide (nmol/L), Testosterone (nmol/L), Dihydrotestosterone (nmol/L), Estrone (pmol/L) and Estriol (pmol/L).
- Assays Used: All serum hormones were determined by established specific direct radioimmunoassays (RIAs).

STATISTICAL ANALYSES AND PHARMACOKINETIC PARAMETERS EVALUATED
- Data Reporting: Mean +/- SEM
- Pharmacokinetic Parameters: Maximum serum concentration measured during a study period of a volunteer (Cmax); time at which Cmax occurred (tmax); terminal elimination rate constant; area under the concentration-time curve from 0-12 hours (AUC 0-12 h)
- Statistical Analysis: AUC 0-12 h as well as tmax and Cmax were calculated and compared by ANOVAwith repeated measurements, t-tests, and Wilcoxon signed rank tests for paired samples. Significance was defined as P < 0.05.

Exposure assessment:

measured

Details on exposure:

DHEA (nmol/L) and two of its metabolites, DHEA-sulfate (umol/L) and 5-alpha-androstane-3-alpha,17-beta-diol-17-glucuronide (nmol/L), were measured in serum collected at -30, 0, 30, 60, 90, 120, and 150 minutes, and 3, 4, 5, 6, 7, 8, 10, 12, and 24 hours after oral administration of DHEA.

Results and discussion

Results:

DEXAMETHASONE SUPPRESSION
- Dexamethasone induced a significant suppression of serum cortisol (to 8% of baseline), of DHEA (18%), DHEA-sulfate (16%), androstenedione (26%), testosterone (28%), dihydrotestostesone (43%), and estrone (54%).

DHEA AND DHEA-SULFATE PHARMACOKINETICS AFTER ADMINISTRATION OF 50 MG / 100 MG DHEA
Oral administration of 50mg DHEA led to restoration of DHEA-sulfate baseline levels, whereas 100 mg induced supraphysiological concentrations.
- Serum DHEA, AUC 0-12 h (50 mg DHEA): 176.1 +/- 21.2 nmol/L x h
- Serum DHEA, AUC 0-12 h (100 mg DHEA): 317.6 +/- 35.3 nmol/L x h
- Serum DHEA-sulfate, AUC 0-12 h (50 mg DHEA): 121.6 +/- 12.3 umol/L x h
- Serum DHEA-sulfate, AUC 0-12 h (100 mg DHEA): 195.4 +/- 8.9 umol/L x h
- Serum DHEA, Cmax (50 mg DHEA): 26.4 +/- 3.8 nmol/L
- Serum DHEA, Cmax (100 mg DHEA): 62.1 +/- 11.4 nmol/L
- Serum DHEA-sulfate, Cmax (50 mg DHEA): 14.9 +/- 1.4 umol/L
- Serum DHEA-sulfate, Cmax (100 mg DHEA): 25.2 +/- 1.5 umol/L
- Serum DHEA, tmax (50 mg DHEA): 2.5 +/- 2.1 h
- Serum DHEA, tmax (100 mg DHEA): 2.4 +/- 0.4 h
- Serum DHEA-sulfate, tmax (50 mg DHEA): 2.9 +/- 0.9 h
- Serum DHEA-sulfate, tmax (100 mg DHEA): 2.8 +/- 0.5 h
- Serum DHEA, t1/2 (50 mg DHEA): 8.9 +/-3.6 h
- Serum DHEA, t1/2 (100 mg DHEA): 7.6 +/- 2.7 h
- Serum DHEA-sulfate, t1/2 (50 mg DHEA): 13.2 +/- 2.7 h
- Serum DHEA-sulfate, t1/2 (100 mg DHEA): 12.1 +/- 2.8 h

Any other information on results incl. tables

OTHER ANDROGENS

- Serum concentrations of dihydrotestosterone were restored to baseline after 50mg DHEA, whereas baseline testosterone and androstenedione levels were only achieved by administration of 100 mg DHEA.

- 50 mg DHEA induced an increase in serum androstenedione concentrations to levels around 60% of baseline, and 100 mg DHEA induced a further increase (tmax for 50 and 100 mg DHEA, 2.6 +/- 1.5 h and 2.6 +/- 0.7 h, respectively) followed by a decrease to levels paralleling baseline concentrations from 6–24 h.

- tmax (testosterone) for 50 and 100 mg DHEA were 3.6 +/- 2.2 h and 2.6 +/- 0.6 h, respectively.

- tmax (dihydrotestosterone) for 50 and 100 mg DHEA were 1.8 +/- 0.7h and 2.6 +/- 0.8 h, respectively.

ESTROGENS

- Serum concentrations of estrone were restored to baseline after 50mg DHEA. 100 mg DHEA increased estrone to levels significantly above baseline.

Applicant's summary and conclusion

Conclusions:

The study concluded that a 50 mg daily dose of DHEA may be a suitable replacement dose in females with adrenal androgen insufficiency. Additionally, the rapid and lasting conversion to potent androgens demonstrated a potential role of DHEA for androgen replacement in females in general (e.g. postmenopausal women). However, the generation of active circulating steroids after DHEA ingestion suggests that DHEA may have possible unfavorable effects in some clinical situations (e.g., hormone-dependent cancer).