Clinical Experience with Norethisterone and Norethisterone Acetate
Authors: G. L. Foss
Journal: BMJ (1960)

The discovery of the 1 9-nortestosterone steroids had made available oral substances for clinical use with a more potent progestational effect than the natural hormone progesterone by injection. Previously, for many years the only oral progestogen was ethisterone ethinyltestosterone, pregneninolone, or anhydrohydroxy progesterone-which was of low potency and about 12 to 15 times less effective than a daily injection of 20 mg. of progesterone for 14 days in producing a full secretory phase in the endometrium (Wied and Davis, 1958). The relationship of these norsteroid progestogens to the naturally occurring hormone in the corpus luteum, and their uses, are discussed by Swyer (1959a). During the last two and a half years experience has been gained with the use of norethisterone ( primolut N ) and more recently with norethisterone acetate. Norethisterone, when given orally in a total dose of 150-200 mg. over 10 days to oestrogen-primed castrated women, or women with secondary amenorrhoea, has been shown to produce a good secretory response in the endometrium (Hertz, Waite and Thomas, 1956; Ober, 1957; Kaiser, 1957; Pots, 1957; Swyer, 1959b). It is, in fact, more potent by this route than progesterone by daily intramuscular injection. Norethisterone acetate was developed by Junkmann (1959), and a dose of 10-40 mg. over 10 days given to oestrogen-primed castrated women likewise produced a full secretory-phase endometrium (Pots, 1958). Although Swyer (1959b), found a dose of 40-80 mg. more certain in this respect, both authors agreed that it was about three more times potent than norethisterone in its effect on the secretory transformation of the endometrium. However, both steroids are of equivalent potency in decreasing oestrogen and pregnanediol excretion (Brown, Fotherby, and Loraine, 1960), and when used to suppress or postpone menstruation Swyer, Sebok, and Barns (1960) found that a larger dose of norethisterone acetate was required. When the present trial started, although the progesta tional dose of norethisterone was reasonably settled and its value established clinically, it was necessary to determine the smallest doses for the effective control of dysfunctional bleeding, when given over many cycles, in order to reduce the cost of long-term treatment. Little was known of the clinical use and value of norethisterone acetate. The objectives of the trial were: (1) to confirm the dose of norethisterone acetate which would develop an oestrogen-primed endometrium into a secretory phase; (2) to observe and compare the clinical effects of both steroids in the treatment of primary and secondary amenorrhoea, the control of dysfunctional menstrual bleeding, and, in a smaller group, the control of oligomenorrhoea and dysmenorrhoea; (3) to observe the effect of norethisterone acetate on the postponement of menstruation. Material and Method The 90 patients in this series were attending the hospital out-patient department or were seen in private practice, and had mostly been referred from gynaeco logists. Thirty-four were given only norethisterone, 21 were given only norethisterone acetate, and the remaining 35 had been treated with both steroids at different times. Norethisterone was available in tablets of 5 mg., and norethisterone acetate in tablets of 2 mg. A series of patients with long-standing amenorrhoea were given oestrogens for 18 days, using tablets of ethinyloestradiol, 0.1 mg. daily, premarin, 1.25 mg. t.d.s., or intramuscular injections of oestradiol mono benzoate, 10 mg. every four days, according to their individual tolerance. After this, norethisterone acetate was given in doses of 2, 4, or 6 mg. daily for 10 days. In a smaller number of similar cases norethisterone was given in doses of 10-15 mg. daily for 6-10 days after oestrogen priming. Endometrial biopsies were then carried out with the use of a Sharman curette, and one or two small strips were taken from the upper portion of the anterior wall of the uterus. These biopsies were taken between the 25th and 32nd days of the cycle as near as possible to the last day of progestogen treatment. Most of the biopsy material was fixed in Bouin's solution at once, except for some which was put into absolute alcohol as suggested by Pots (1959, personal communication), However, this method was abandoned owing to the degree of desiccation with distortion of the endometrium. Sections were stained with haematoxylin and eosin.