Seppo Sipinen

Different effects of two progestins on plasma high density lipoprotein (HDL2) and postheparin plasma hepatic lipase activity.

Two progestins with different androgenic activity were compared for their effects on plasma high density lipoproteins and postheparin plasma lipase activities in premenopausal women. Levonorgestrel, a nortestosterone-derived steroid with androgenic activity reduced plasma HDL cholesterol by 17% (P less than 0.05) and HDL2 cholesterol by 30% (P less than 0.05), without changing the HDL3 cholesterol concentration. At the same time the postheparin plasma hepatic lipase activity was increased by 56% (P less than 0.01) whereas the lipoprotein lipase was not changed. None of these effects was reproduced during administration of medroxyprogesterone acetate, a progestin with low androgenic activity. The results suggest, first, that the decrease of HDL cholesterol observed during treatment with progestins is related to the androgenic activity of the steroid used, and, second, that the change in HDL (HDL2) is caused by androgen-induced increase of hepatic lipase activity.

Post-menopausal hormone replacement therapy: effects of progestogens on serum lipids and lipoproteins. A review

Until a few years ago, post-menopausal hormone replacement therapy was based on oestrogen alone. There was a general feeling that oestrogen, if it had any effect at all on the risk of coronary heart disease (CHD), was probably beneficial as long as conventional doses of natural oestrogen were used [1,2]. Some studies indicated quite convincingly that the menopause was associated with an increased risk of coronary heart disease [3,4]. Moreover, published data suggested that this risk could be diminished by oestrogen substitution [5,6], although this was not confirmed by all studies [7,8]. Post-menopausal oestrogen replacement therapy was found to be associated with ‘beneficial’ effects on at least two major CHD risk factors: high-density lipoprotein (HDL) cholesterol was increased and low-density lipoprotein (LDL) cholesterol was decreased by oestrogen treatment [9-111. The magnitude of the fall in LDL cholesterol was directly proportional to the initial LDL cholesterol level, suggesting that oestrogen could be the drug of choice in the treatment of postmenopausal hypercholesterolaemia lipid disorder [ 121. The recent recommendation (for review, see [13]) that sequential progestogen should be added to cyclic oestrogen therapy in order to reduce the risk of endometrial cancer has greatly increased the use of progestational agents ‘by postmenopausal women. Since many of the effects of oestrogen, including changes in lipoproteins, are opposed by some progestogens, great interest has been focused on the potential merits and demerits of combining progestogens with oestrogen. In this review we attempt to summarise current knowledge concerning the effects on serum lipids and lipoproteins of progestogens used either alone or as a supplement to post-menopausal oestrogen replacement therapy.

Reduction of plasma high-density lipoprotein2 cholesterol and increase of postheparin plasma hepatic lipase activity during progestin treatment

Twenty-seven menopausal women were given the synthetic progestin levonorgestrel for two weeks. The mean plasma high-density lipoprotein (HDL) cholesterol concentration decreased from 1.32 mmol/l to 1.01 mmol/l (p less than 0.001) during treatment. This was due to the selective reduction in plasma HDL2 cholesterol from 0.73 mmol/l to 0.44 mmol/l, whereas the plasma HDL3 cholesterol was not changed. The mean hepatic lipase (HL) activity of postheparin plasma increased from 20.6 to 35.3 mumol.h-1.ml-1 (p less than 0.001) while the lipoprotein lipase (LPL) activity was not changed. A significant inverse correlation existed between the HDL2 cholesterol concentration and HL activity both before (r=-0.49, p less than 0.01) and after (r=-0.39, p less than 0.05) treatment, and a significant correlation was observed between the changes in these two variables (r=0.39, p less than 0.05). These results are compatible with the hypothesis that HL participates in the regulation of plasma HDL2 levels and they suggest that progestin treatment reduces plasma HDL2 cholesterol concentration by increasing the hepatic lipase activity. It is not known whether this type of HDL2 reduction is accompanied by increased atherogenesis but as long as the issue is unresolved some caution is needed in the long-term use of levonorgestrel, particularly in women who simultaneously are given some other drug depressing plasma HDL2 concentration.

Return of Ovulation After Abortion and After Discontinuation of Oral Contraceptives

The return of ovulation after abortion and discontinuation of oral contraceptives was determined by plasma progesterone measurements. Plasma samples were obtained from 67 women at 3 to 6 weeks after abortion and in two groups of postabortion women at 3 to 6 weeks after cessation of oral contraceptives. In the first of these latter two groups, 50 women started taking the pills (containing 30 microgram of ethinylestradiol and 150 microgram of levonorgestrel) immediately after abortion, and the second group of 29 women started taking the pills from the first postabortion menses. Ovulation had recurred in 34% of the women 3 weeks after abortion and in 78% of the women at 6 weeks. The return of ovulation had occured in approximately 55% at 3 weeks after cessation of oral contraceptives in both groups. At 6 weeks after cessation, approximately 85% of women had ovulated in both groups. Luteal function in these two groups was found to be equal and was significantly better in both groups than during the first postabortion cycle (P < 0.005). It is concluded that the early return of ovulation after abortion makes it necessary to commence effective contraception immediately after abortion. The immediate administration of oral contraceptives after abortion does not affect the return of ovulation after discontinuation of oral contraceptives.

Post-heparin plasma hepatic lipase activity as predictor of high-density lipoprotein response to progestogen therapy: studies with cyproterone acetate.

Cyproterone acetate (CPA) was administered to 13 menstruating women from day 14 to day 27 of the cycle at a dose of 5 mg/day. Serum lipoprotein lipid levels and postheparin plasma lipase activity were determined on day 27 of the cycle before treatment and during two treatment cycles. No significant changes were observed in hepatic lipase activity or in very-low-density (VLDL) or low density lipoprotein (LDL) concentrations. However, analysis of high-density-lipoprotein (HDL) subfractions by precipitation demonstrated a significant reduction in HDL2 cholesterol (-24%, P less than 0.05) during cyproterone acetate treatment. It is suggested that this change is related to oestrogen deficiency induced by inhibition of luteinizing hormone (LH) secretion.

An oestrone-releasing vaginal ring in the treatment of climacteric women

Post-menopausal patients were treated with a new form of oestrogen administration by using two types of oestrone-containing vaginal rings. It was observed that oestrone was absorbed from the vagina as demonstrated by elevated plasma concentrations of oestrone (E1) and oestradiol (E2). In 3 out of 4 patients the ratio of E1/E2 was 4-5 in the first plasma samples collected after the initiation of the treatment. After the first week of treatment this ratio had dropped to 0.8-1.5, which indicates an increase and stabilization in the conversion of oestrone to oestradiol within 1 wk of treatment. The high levels of plasma oestrogens were associated with a decrease of plasma gonadotrophins and the disappearance of climacteric symptoms. The first type of ring tested resulted in a high initial burst of oestrone release, as evidenced by high concentrations of oestrone and oestradiol during the first 2 wk. In the second type of vaginal ring the high initial oestrone release was not present and the plasma oestrone and oestradiol levels were stable. The patients tolerated the treatment well, and after gaining experience, easily accepted this route of self-administration. It seems that the vaginal silastic ring is an effective steroid-delivery system in post-menopausal women. As judged by plasma oestrone and oestradiol profiles, it seems that the second type of ring was preferable to the first one as an intravaginal releasing device.

Postmenopausal oestrogen replacement therapy with subcutaneous oestradiol implants

Ten postmenopausal patients were treated by means of subcutaneous oestradiol-releasing silastic implants. Half of the patients received 3 implants, each containing 12 mg oestradiol valerate (E2V), while the other half received 4 implants, each containing 27 mg oestradiol benzoate (E2B). Progestogen was added to the treatment for 14 days, 6 weeks after implant insertion and every fourth week thereafter. Serum levels of oestrone (E1), oestradiol (E2), follicle-stimulating hormone (FSH) and luteinizing hormone (LH) were followed up. The effects on endometrial thickness, uterine volume and breast tissue were evaluated by ultrasound, mammography also being used for breast examination. The follow-up period was 24 weeks, but the implants were not removed until the climacteric symptoms reappeared. E1 and E2 levels remained higher and gonadotrophin levels lower than the pretreatment values during the 24-week follow-up period. Oestrogen effects were seen in both the uterus and the breasts. Both types of implant were effective in relieving climacteric symptoms. The mean time for symptom return was 10 months (range 6-18 months) in the E2V group and 8 months (range 4-12 months) in the E2B group. Our results indicate that nonbiodegradable controlled-release oestrogen implants offer a safe, effective, convenient and well-accepted alternative means of administering oestrogen replacement therapy.

Pharmacokinetic Studies on Low Dose Estradiol 17β Administered Orally to Postmenopausal Women

Peripheral plasma from four postmenopausal women was analysed for estrone, estradiol, luteinizing hormone and follicle stimulating hormone during 24 hours following an oral intake of a single dose of 1.0 mg micronized estradiol, on the first day of therapy and after one month. A similar study was carried out with another four postmenopausal patients, who received 0.2 mg estradiol three times daily. The measurements were performed by radioimmunoassay (RIA).

Silastic implants releasing estrone in the treatment of climacteric complaints

A study on continuous low-dose estrone treatment achieved with two different silastic implants is presented. In the study estrogen treatment was supplemented with the addition of progestin in three different modes of application. The measurements of plasma estrone and estradiol concentration showed a 3- to 6-fold and a 2- to 3-fold increase, and that of FSH a decrease of 25%. The measurements of plasma estrone gave concentrations of 200-400 pg/ml and plasma estradiol was 70-200 pg/ml with uncovered estrone-releasing implants after 4 wk of treatment. The ratio of plasma levels of estrone/estradiol was around 3. The initial high estrone concentration after implantation could be eliminated by covering the rods with a thin layer of neutral silastic material. Plasma FSH and LH concentration significantly depressed when the estrone treatment was combined with levonorgestrel-releasing implants. The insertion of estrone-releasing implants alone and in combination with the cyclic treatment with norethindrone perorally, or with a norgestrienone-releasing silastic vaginal ring suppressed only the plasma FSH concentration. The climacteric complaints disappeared in a few days in every patient treated with uncovered estrone-releasing implants. Because it is easy to remove when required, the treatment with estrone-releasing silastic implants can be regarded as being safe for the patients.