Endometrial safety of a novel monophasic combined oral contraceptive containing 0.02 mg ethinylestradiol and 2 mg chlormadinone acetate administered in a 24/4-day regimen over six cycles.
BACKGROUND
This study was conducted to examine whether small doses of ethinylestradiol (EE, 0.02 mg) and chlormadinone acetate (CMA, 2 mg) administered in a novel 24/4-day regimen during six cycles would suffice to suppress proliferation and to cause secretory changes in the endometrium.


METHODS
This Phase II, randomized (two assessment groups), single-center, open, uncontrolled, multiple-dosing study treated 59 female subjects. The subjects underwent three endometrial biopsies: one pretreatment, one during medication (either at Cycle 3 or Cycle 6) and one during the first post-treatment cycle.


RESULTS
The study revealed that 0.02 mg EE/2 mg CMA effectively transformed the endometrium from a proliferative state into a secretory or inactive state after three (90% of subjects) and six (76% of subjects) medication cycles. The mean endometrial thickness decreased markedly from 10.2 (SD±3.0) mm (pretreatment) to an unfavorable level for the nidation of a blastocyst [5.3 (SD±2.1) and 4.1 (SD±2.2) mm in Medication Cycles 3 and 6, respectively]. Correspondingly, estradiol and progesterone levels decreased during treatment. In the post-treatment cycle, endometrial biopsy and ultrasound evaluation as well as sex hormone levels suggested a quick return to fertility. There were no signs of hyperplasia, endometrial polyps, neoplasia or other detrimental histopathological changes at any time during the trial. Treatment-related adverse events (AEs) were reported by 22 (37%) of 59 subjects and were reported most commonly in Cycle 1, decreasing continuously thereafter. No AEs led to discontinuation of the trial medication and there were no serious AEs.


CONCLUSIONS
The 24/4-day regimen of 0.02 mg EE/2 mg CMA provided effective and reversible endometrial effects with secretory transformation or suppression without inducing pathological changes.
Rabe
Thomas
T
University Women's Hospital, Heidelberg, Germany. thomas.rabe@med.uni-heidelberg.de
Hartschuh
Elena
E
Wahlstrom
Torsten
T
Höschen
Kornelia
K
König
Simone
S
D000328:Adult; D002715:Chlormadinone Acetate / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D003277:Contraceptives, Oral, Combined / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D003280:Contraceptives, Oral, Synthetic / Q000009:adverse effects / Q000494:pharmacology*; D004717:Endometrium / Q000187:drug effects* / Q000473:pathology; D004967:Estrogens / Q000009:adverse effects / Q000494:pharmacology*; D004997:Ethinyl Estradiol / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D005260:Female; D006801:Humans; D055815:Young Adult
D003277:Contraceptives, Oral, Combined; D003280:Contraceptives, Oral, Synthetic; D004967:Estrogens; D002715:Chlormadinone Acetate; D004997:Ethinyl Estradiol