British Journal of Obstetrics and Cynaecology December 1975. Vol82. pp 987-991

CORTISOL METABOLISM AFTER ORAL CONTRACEPTIVES: TOTAL PLASMA CORTISOL AND THE FREE CORTISOL INDEX BY

T. G . BRIEN Department of Pathology, University College, Dublin

Summary Plasma concentrations of cortisol, cortisol resin uptake ratio (cortisol RUR) and free cortisol index (FCI) were measured in women taking combined oestrogen/ progestogen and progestogen only oral contraceptives. Compared to control subjects, women taking the combined pill had elevated cortisol and cortisol RUR values in both the morning and afternoon but there was no significant change in FCI. Women taking the progestogen only pill had essentially normal levels of cortisol, cortisol RUR and FCI at both times of the day. As far as could be judged, diurnal variation of total cortisol and FCI remained unimpaired in women taking both types of pill. The FCI measurements indicated that there was no significant increase in metabolically active cortisol in women taking either the combined oestrogen/progestogen or the progestogen only type of oral contraceptive. THE rise in plasma cortisol induced by the administration of oestrogens was first documented by Taliaferro et a1 (1956) and shortly afterwards confirmed by Wallace et al (1957). Mills et a/ (1960) showed that this rise in plasma cortisol could be attributed to the protein bound fraction alone and concluded that the absolute amount of free cortisol remained essentially unchanged. It has also been shown that administration of oestrogen causes an increase in the plasma concentration of a specific binding protein, namely, corticosteroid binding globulin or CBG (Slaunwhite and Sandberg, 1969; Musa et al, 1967). Confirmation that the increase in total plasma cortisol is due to an increase in the moiety bound to CBG and that the levels of free or metabolically active cortisol are normal is found in the work of O’Connell and Welsh (1969) and Burke (1970). Free or unbound plasma cortisol has hitherto been measured by the cumbersome techniques of either pressure dialysis (Murray, 1967), ultrafiltration (Peterson et a/, 1960) or gel

filtration requiring 25 ml of plasma (Burke, 1969~).The recently devised free cortisol index or FCI (Brien and Hingerty, 1975; Baumann et al, 1975) is a simple method of obtaining an indirect measure of the free or non-protein bound plasma cortisol and bears the same relationship to cortisol as the free thyroxine index does to thyroxine. In the present study the FCI was measured in women taking oral contraceptives of both the combined oestrogen/progestogen and the progestogen only type, to determine whether the FCI could give a suitable measure of true adrenocortical status-unlike the total plasma cortisol by conventional methods-and to establish a base line against which changes in adrenocortical status could be measured without the necessity for discontinuing contraceptive medication. AND METHODS MATERIALS Subjects. Subjects consisted of 43 healthy women who had been taking oral contraceptives

987

988

HRIEN

TABLEI Drugs used by patients in study Brand name

Oestrogen

Progestogen

Minilyn Minovlar

Ethinyl oestradiol 50 pg Ethinyl oestradiol 50 pg

Neogynon Ovran Noriny l-I Ortho-Novin 1/50 50 Ovulen

Ethinyl oestradiol 50 pg Ethinyl oestradiol 50 pg Mestranol 50 pg Mestranol 50 tLg Ethinyl oestradiol 50 pg

Gynovlar

Ethinyl oestradiol 50 pg

Lynestrenol Norethisterone acetate d-Norges terol d-Norgesterol Norethisterone Norethisterone Ethynodiol diacetate Norethisterone

Micronor Noriday

None None

Norethisterone 0.35 mg Norethisterone 0.75 mg

for at least six months together with a control group of 16 who were taking no medication. Details of the oral contraceptives in use are given in Table I. Morning blood samples were taken at about 1100 hours and afternoon samples at about 1500 hours. Methods. The cortisol resin uptake ratio (cortisol RUR) and FCI were determined according to methods previously described (Brien and Hingerty, 1975) except that for this study plasma cortisol was estimated by a competitive protein binding technique (Baum et al, 1974) using a commercially available kit (Cortipac, Radiochemical Centre, Amersham). Statistical comparisons were carried out using Student’s “t” test. RESULTS Results of cortisol, cortisol RUR and FCI determinations are shown in Table I1 while statistical comparisons are given in Table 111. Figure 1 shows the distribution of morning cortisol, cortisol RUR and FCI values in the oestrogen treated group. In the combined oestrogen/progestogen treated group both cortisol and cortisol RUR values were significantly elevated compared to control values in both the morning and afternoon but at neither time was the relatively small rise in FCI values statistically significant. On the other hand significant increases in all three parameters were seen when the oestrogen/progestogen treated group was compared with the progestogen only group.

2 . 5 mg

1.0mg 0.25 mg 0.25 mg 1.0 mg 1.o n1g 1.0mg 3.0 mg

i

401I

I

Cortisol ug

YO

Cortisol R U R

FCI

FIG. I Cortisol, cortisol RUR and FCI in women taking combined oestrogen-progestogen preparations. Dashed lines indicate normal limits.

CORTISOL METABOLISM WITH CONTRACEPTIVES

989

TABLE I1 Plasma cortisol, FCZ and cortisol RUR in patients in study

N

Group

Combined Progestogen only Control Combined Progestogen only Control

a.m. a.m. a.m. p.m. p.m. p.m.

14 6 16 23 6 10

Cortisol RUR

Cortisol (rg per 100 ml)

FCI

Mean iSD

Mean 1SD

Mean SD

1.401 0 . 1 5 1.09k0.14 0.99 1 0 . 0 9 1 - 5 1k0.20 1 .16 +O .07 1.06k0.12

28.10*7.73 13.48A3.40 16.49 i 4 . 8 5 22.78 f6.50 9.47 i2.81 13.92f4.18

20,1415.34 12.3812.94 17.00 1 5 . 99 15.1453.84 8.1912.28 13.61&5.92

TABLE111 Statistical analysis of results presented in Table Ii Plasma cortisol Combined Combined Combined Progestogen Progestogen Control Combined Combined Progestogen

a.m. v Control a.m. v Progestogen a.m. v Oestrogen a.m. v Control a.m. v Progestogen a.m. v Control p.m. v Control p.m. v Progestogen p.m. v Control

a.m. a.m. p.m. a.m. p.m. p.m. p.m. p.m. p.m.

PtO.001 P