Metabolic and clinical effects of progestogens

Synthetic progestogens differ not only in their hormonal potency, but also in their spectrum of hormonal activities. Beside their progestogenic and anti-oestrogenic effects, they may exert oestrogenic, androgenic, antiandrogenic, glucocorticoid and/or anti-mineralocorticoid activities. Consequently, progestogens may influence various metabolic parameters and modulate oestrogen-induced alterations in lipid metabolism, haemostasis, and various other factors. Progestogens with androgenic properties may counteract ethinyloestradiol (EE)-induced changes in lipoprotein metabolism, but do not cause atherosclerosis in the presence of EE. Oral contraceptives (OCs) containing androgenic progestogens which attenuate the EE-dependent changes in haemostasis, may be associated with a lower risk of venous thromboembolic disease than OCs whose progestogens have a less androgenic profile. Progestogens with androgenic activity may also antagonize oestrogen-induced alterations in various other hepatic proteins and modulate the effect of EE on growth factors. Progestogens with antiandrogenic activity may enhance the beneficial effect of EE in women with hyperandrogenic manifestations. Progestogens with glucocorticoid effects may increase procoagulatory activity in the vessel wall, while progestogens with anti-mineralocorticoid activity may reduce the aldosterone-induced water-retention in some women. For most women the differences in the hormonal pattern of progestogens used in OCs are without clinical relevance, but may be useful for women predisposed for the development of certain disorders.     

Absorption and metabolic effects of different types of estrogens and progestogens

The classes of estrogens and progestogens currently in use and their routes of administration have been considered. The decision to prescribe any given estrogen or progestogen and by a particular route has a significant impact on cardiovascular risk factors. Among the estrogens, native estradiol and estrone are favored over equine and synthetic estrogens. Given this choice, oral and systemic routes of administration are not sufficiently different clinically to endorse one method over the other, except for the unusual hypertensive woman or the patient with a history of thromboembolic phenomena. Among the progestogens, oral micronized progesterone offers much promise for use in postmenopausal women. However, the oral use of lower doses of other progestogens seems appropriate at the present time. With the availability of oral micronized progesterone and in time a transdermal system, the need for alternate routes of administration for other progestogens seems unnecessary.     

The effects of estrogens and progestogens on the endometrium. Modern approach to treatment

The major hazard of postmenopausal cyclic estrogen therapy is endometrial hyperstimulation. The incidence of hyperplasia is dose dependent; the incidence of carcinoma is both dose and duration dependent. The risk of carcinoma is small. Invasive procedures such as endometrial biopsy to detect those patients with hyperplasia and carcinoma are unlikely to be cost-effective and have other disadvantages. With cyclic estrogens, biopsies should be performed at regular intervals irrespective of the bleeding pattern. The possible alterations to cyclic treatments to reduce the risk of endometrial hyperstimulation have been reviewed; only progestogen addition has been shown to be effective. Maximal effects are obtained when progestogens are added for 12 to 13 days each calendar month. To reduce the risk of side effects, the minimum dose of progestogen should be prescribed, and with the nor-testosterone derivatives, a small dose of norethindrone, approximately 1 mg daily, is as effective as 5 mg daily. The smaller doses cause minimal lipid changes. Interpatient variation in response to the 17-hydroxyprogesterone derivatives can occur, and at high doses, adverse lipid effects have been reported. With sequential estrogen/progestogen therapies, the endometrial histology appears to correlate with the bleeding pattern, thereby, perhaps, obviating the need for biopsy. The development of regimens to induce endometrial atrophy and amenorrhea is suboptimal, and further research is required.     

Estrogens, progestogens and endometrial cancer.

At the Wilford Hall U.S. Air Force Base Medical Center, Texas, about 4000 postmenopausal women received estrogen replacement therapy during 1975. Of these, 2700 took estrogens only and 1240 were given a progestogen along with estrogen. Hysterectomy had been done previously on 1700 patients (42%), leaving 2300 with intact uteri and a risk of endometrial cancer. Adenocarcinoma of the endometrium was diagnosed in 7 patients. Of these, 6 had received estrogen therapy. There was 1 endometrial malignancy in a patient also receiving a progestogen. Among 510 untreated postmenopausal women with intact uteri, 1 adenocarcinoma of the endometrium was found. Type and dosage of estrogen were unrelated to endometrial malignancy. In addition to the 7 endometrial cancers from the clinic, 22 cases were diagnosed elsewhere and referred for treatment, 11 of these had received no hormones. 10 were taking estrogens and 1 was receiving Oracon for birth control. The incidence of endometrial malignancy in the U.S. is reported to be 21/100,000 women/year. There is a 3-fold to 9-fold increased risk of endometrial cancer associated with obesity alone. The probability that untreated postmenopausal women with intact uteri will develop carcinoma of the endometrium is 1/1000/year. With estrogen users, it is reported to be increased -7.6/1000 women/year. In the author's clinic during 1975, the incidence among those receiving only estrogen was 4.7/1000. Among those also receiving a progestogen the incidence was .8/1000. Unopposed estrogens apparently have a role in the etiology of endometria hyperplasia and neoplasia through incomplete shedding of the endometrium. Progesterone produces more complete sloughing of the endometrium and also converts all degrees of hyperplasia into secretory endometrium. Nulliparity, infertility, and anovulation are predisoposing factors to endometrial carcinoma. Progestogens are palliative therapy for endometrial cancer.     

The effects of transdermal oestradiol and oral progestogens on haemostasis variables

Objective To evaluate the effects of 1 g (1 mg oestradiol) transdermal oestradiol gel continuously combined with 10 mg medroxyprogesterone acetate orally 12 days either monthly or every third month on haemo- stasis variables.
Design An open, parallel stratified study.
Setting Sahlgrenska University Hospital, Goteborg, Sweden
Participants A total of 48 peri- and postmenopausal women less than 65 years of age participated in this study. Twenty-seven women, who had from 2 months to 3 years since their last period were included in group I. Twenty-one women, who were more than 3 years postmenopausal, comprised group II.
Main outcome measures The following parameters were determined: von Willebrand factor antigen, factor VII antigen, fibrinogen, antithrombin, protein C, protein S, plasminogen activator inhibitor activity, tissue plasminogen activator antigen, prothrombin fragment₁₊₂, thrombin-antithrombin complex and platelets.
Results Both regimens decreased fibrinogen, factor VII antigen as well as antithrombin.
Conclusions These changes were mainly 'in an anti-thrombotic direction'. The overall impression is that the transdermally administered oestrogen in combination with an oral progestogen induced favourable, although slight changes in the haemostatic system. The possible influence of these changes on the risk of cardiovascular disease remains yet to be studied.     

Effects of long-term estrogen replacement therapy. I. Metabolic effects.

Two groups of hypoestrogenic women are analyzed by retrospective comparisons. Patients were observed by a single group of physicians for at least five years; 301 patients were treated with replacement estrogen and 309 patients were untreated. Incidence figures for various metabolic diseases present at entry and both during and after estrogen therapy were compared by the usual statistical analysis and by statistical adjustments for certain group differences (Mantel-Haenszel statistic). The long-term administration of estrogen to these relatively young women with hypoestrogenism was associated with significantly lower rates of development of cardiovascular disease, hypertension, osteoporosis, and fractures. Detrimental effects were a higher rate of abnormal uterine bleeding and an increase in the likelihood of developing adenocarcinoma of the endometrium. Effects of estrogen preparation, dosage, method of therapy, duration of therapy, and the addition of synthetic progestins are presented.     

Differential effects of transdermal estradiol and sequential progestogens on impedance to flow within the uterine arteries of postmenopausal women.

OBJECTIVE: To investigate the relationship between estradiol (E2), progestogen, and impedance to blood flow in the uterine artery. SUBJECTS: Twelve postmenopausal women treated for two cycles with transdermal E2, 0.05 mg/d, with either norethindrone acetate, 0.7 mg, or medroxyprogesterone acetate, 10 mg added sequentially. MEASUREMENTS: Transvaginal ultrasonography and color flow imaging were used to measure the pulsatility index in the uterine arteries before and during the E2-only and combined E2/progestogen phases. RESULTS: The mean pulsatility index fell to 53% of its pretreatment value within 12 days E2 administration (P < or = 0.0001) and was 66% of its pretreatment value in the combined phase (P < 0.005). Similar changes were seen in cycle 2. Time since menopause was correlated with the pretreatment pulsatility index (r = 0.674, P < 0.05) and change in pulsatility index on treatment (r = 0.856, P < 0.001). CONCLUSION: Gonadal hormones have a profound effect on arterial tone in postmenopausal women; this action may help explain some of the beneficial effects of estrogen on arterial disease risk.     

Metabolic effects of infection and postnatal steroids

Optimal development of the newborn depends on rapid accretion of substrate in the neonatal period, particularly in the premature infant. Steroids and infection not only induce catabolism, but associated endogenous responses reprioritize crucial substrate to restore homeostasis. The result is a protein/energy deficit and concomitant delay in growth and development. Innovative feeding strategies and novel therapies are needed to reduce the impact of catabolism in this population.     

Metabolic effects of beta-sympathomimetic drugs and dexamethasone in normal and diabetic pregnancy.

Marked hyperglycaemia and hyperinsulinaemia were observed in two normal women in premature labour treated with an intravenous infusion of a beta-sympathomimetic drug and intramuscular dexamethasone injections. Similar therapy in a chemical diabetic patient caused diabetic ketoacidosis, while treatment of an insulin dependent diabetic with dexamethasone alone resulted in a major increase in her insulin requirements. It is suggested that the diabetogenic effects of beta-sympathomimetic drugs and dexamethasone may be additive and that regular plasma glucose estimations should be made when they are used, especially in patients with impaired glucose tolerance.     

Use of progestogens in postmenopausal women

Estrogen therapy for postmenopausal women has received adverse publicity since the mid-1970s because several reports linked estrogens with an increased risk of endometrial cancer. Other studies indicated that the risk of endometrial malignancy is reduced when a progestogen is added to the estrogen replacement. Not all postmenopausal women need estrogen replacement. Because some continue to produce significant amounts of endogenous estrogens, many need progestogen replacement to reduce the risk for endometrial hyperplasia and adenocarcinoma. It has been well demonstrated that estrogen replacement therapy does not increase the risk for breast cancer. However, added progestogen may actually reduce the risk for this malignancy in some women. Where estrogen therapy retards the development of and helps to prevent osteoporosis, added progestogen may restore bone which has been lost by promoting new bone formation. The greatest benefit to accrue to postmenopausal estrogen users is prevention of cardiovascular disease. Concern has been expressed that added progestogen may negate this benefit by adverse effects on lipids. Side effects of added progestogen occur, but these may be managed by changing to another progestogen or adding a mild diuretic.     

Use of progestogens in pregnant and infertile patients

Progesterone is an essential hormone in the occurence and maintenance of pregnancy. Natural or synthetic progestogens are commonly used in pregnant patients or patients undergoing infertility treatments for various indications. Most frequently put indications for the use of progestogens in these patient populations are the prevention of spontaneous preterm birth, the prevention of pregnancy loss in pregnancies with an unexplained recurrent pregnancy loss and in patients with threatened abortion. It is also used in pregnant women undergoing nonobstetric surgery, for infertility or recurrent pregnancy loss that is thought to be due to luteal phase defect or as a luteal support in stimulated IVF cycles. We aimed to review the current evidence for the use of progestogens in each of these settings.