Antiandrogenic progestins for treatment of signs of androgenisation and hormonal contraception

For treating signs of androgenisation (seborrhoea, acne, hirsutism, alopecia) ethinylestradiol in combination with an antiandrogenic progestin is the treatment of choice in adolescents and females throughout the reproductive years, since these combinations are also highly suitable for contraception. Under long-term treatment a favourable effect on carbohydrate and lipid metabolism can be seen due to the antiandrogenic properties of the progestins. These combinations also correct menstrual cycle disturbances and thus reduce the incidence of anaemia. In addition, the frequency of dysmenorrhoea and pelvic inflammatory disease will be lowered and there is a reduction in the risk of endometrial and ovarian cancer.     

Role of radiology in intrauterine contraception

The authors discuss the merits of some indications of radiological explorations during intra-uterine contraception. In reference to systematic hysterograms performed in order to measure the uterine cavity or screen malformations, they feel that, because of the fact that most copper intra-uterine device are currently standard and considering the rare occurrence of uterine malformations (1.5 to 2.5%), these explorations do not seem any longer justified, as they considerably increase the cost of intra-uterine contraception.     

Role of progestins with partial antiandrogenic effects.

An experts' meeting on the 'Role of progestins with partial antiandrogenic effects' was held in Berlin from January 19 to 22, 2001. The meeting was chaired by Dr R. Sitruk-Ware (New York, USA) and participants included Ms F. Fruzzetti (Pisa, Italy), J. Hanker (Trier, Germany), J. Huber (Vienna, Austria), F. Husmann (Bad Sassendorf, Germany), S. O. Skouby (Copenhagen, Denmark), J. H. H. Thijssen (Utrecht, The Netherlands), and R. Druckmann (Nice, France). The present paper reports the conclusions of the meeting. However, the publication of the Women's Health Initiative study, which appeared after the meeting, led to additional comments and revisions.     

Progesterone and progestins

There are 2 main types of synthetic progestogens: progestogens derived from progesterone and progestogens derived from testosterone. Besides these 2 kinds of progestogens, some steroids have a progestative activity. The characteristics and indications of these various progestogens are examined. The role of progesterone in sterility, contraception and treatment of dysovulation and menopause is described. Progesterone and the various progestogens each have theoretical indications derived from their specific properties. Progesterone represents the most logical treatment for dysovulation, and the safest complement in post-menopause estrogenotherapy. However progesterone is efficient in contraception only for its local effects. Progestogens derived from progesterone are not very suitable for oral contraception and their metabolic side-effects justify their exclusion from estro-progestative contraception. Progestogens derived from testosterone are best adapted to oral contraception although they have some clinical and metabolic side effects. They are inefficient and probably dangerous in the treatment of sterility or during pregnancy. Because of their metabolic side effects, they are not very suitable for the treatment of post-menopause.     

Disadvantages of third generation progestins

Many publications have been dedicated to the mode of action, efficacy, and secondary effects of oral contraceptives (OCs). Healthy OC users neither accept side effects nor find them acceptable. In most, the level of effectiveness and the incidence of side effects are proportional to the total dose of steroids in the OC combination, the balance between the estrogen and progestin content, and the specific properties of the compounds. Cardiovascular events in OC users were first attributed to the ethinyl estradiol dose and, as a first step, the estrogen dose has been reduced in OCs produced since the 1970s. Next, the vascular risk has been correlated with changes in the lipid profile. Progestins with androgenic properties have been incriminated in unexpected vascular events because of their adverse effect on the lipid profile. In pursuit of minimizing these secondary effects and to favorably change lipid patterns, some new progestins without androgenic properties have been developed and are available in Europe. These new compounds, third generation progestins, are derived from levonorgestrel. These progestins belong to the gonane category and, because of their molecular structure, are capable of attaching themselves to the androgen receptor. They include gestodene, desogestrel, and norgestimate. The study of changes in the pattern of protein markers of the sex hormone binding globulin (SHBG) suggests very weak biological androgen activity when these progestins are administered with ethinyl estradiol. Likewise, the anti-estrogenic action of these progestins which have lost their partial androgenic effect is reduced. When these progestins are administered with the ethinyl estradiol, they do not obstruct the estrogenic effect on the level of protein markers, e.g., SHBG and high density lipoprotein. Although this effect is considered beneficial, the reduced estrogenic activity on antithrombin III, triglycerides, and perhaps target tissues may be considered a non-negligible disadvantage of the third generation progestins in the most recent OCs.     

Clinical profile of contraceptive progestins

The term progestogen has been widely utilized to indicate the general class of agents that includes both progesterone and its synthetic analogs, whereas the term progestin refers only to synthetic progestational steroids. The development of progestins has been influenced in a major way by the search for orally active hormonal contraceptives, since it is likely that hormonal contraceptives will continue to utilize a progestin, the only possible alternative being represented by the utilization of antiprogestins. Synthetic progestogens in clinical use today belong to three main chemical families: progesterone derivatives (progesterone, retro-progesterone, 19-norprogesterone and 17α-hydroxyprogesterone); gonane and 19-nortestosterone derivatives (norethisterone, levonorgestrel, desogestrel, gestodene, norgestimate); a spironolactone derivative. Biological potency of progestogens varies depending on the end-point measured, usually ovulation inhibition and endometrial transformation; with both these tests, the most active compounds are all gonane derivatives, with a potency over a 100 times that of the natural hormone. When administered in adequate doses, a progestin inhibits fertility by inhibiting ovulation. This action is mainly exerted at the hypothalamic level where, physiologically, progesterone decreases the number of LH pulses. When progestogens are delivered directly to the uterine cavity, their action seems to be purely local. It has been amply proven that - even when administered in doses that do not constantly inhibit ovulation - a progestin can still remain effective as a contraceptive by acting at the level of the cervical mucus and, at least in part, of the endometrium. Progestogens utilized today differ largely in their pharmacokinetics. In general, after intake, these compounds are rapidly absorbed and distributed so that peak serum concentrations are reached between 1 and 4 h. Third-generation progestins (desogestrel, gestodene, norgestimate) have common characteristics: a higher affinity for progesterone receptors than their predecessors, a lower affinity for androgen receptors, a higher selectivity of action, a higher central inhibitory activity, a higher potency at the level of the endometrium, and an overall metabolic neutrality, in terms of effects on lipid and carbohydrate metabolism. In general, progestins can induce two types of adverse effects: changes in lipid metabolism and bleeding irregularities. Whereas the newer compounds seem to have overcome the first of these adverse effects, the second remains untouched: to this day, proper cycle control can only be achieved with combined hormonal contraceptives.     

Endometrial hyperplasia treated by progestins

This study of 16 patients compares treatment for adenomatous or atypical hyperplasia with one of three schedules of oral progestational drugs. Treatment of endometrial hyperplasia with megestrol, 80 mg daily for 6 weeks, was not satisfactory with the first 5 patients. Treatment was then prolonged to 9 weeks and 4 additional patients so treated. Another 7 patients were treated with medroxyprogesterone acetate (Provera), 80 mg daily for 6 weeks. All medication was given orally. Patients ranged from 36 to 60 years of age with parity from 0 to 10. Endometrial biopsies were done at intervals. All but 1 had a complete remission under therapy. This patient's endometrium progressed from atypica to carcinoma in situ. At hysterectomy glandular hyperplasia with focal carcinoma in situ in the endometrium, adenomyosis, and cellular leiomyomas were found. Remissions persisted only in 5, the longest period being 4 years. Hysterectomy was required in 6. None developed invasive carcinoma. Patients are mildly symptomatic. It is thought that continuous progestational treatment for indefinite periods may be necessary if hysterectomy is to be avoided.     

Origin of serum progestins in polycystic ovarian disease

The glandular origin of excess circulating steroid hormones in women with polycystic ovarian disease has been difficult to establish with previously described perturbation techniques. Recently it was demonstrated that daily administration of a potent gonadotropin-releasing hormone agonist achieves complete and reversible suppression of ovarian steroid secretion. To examine the source of C-21 steroid hormones, circulating levels were measured before and after administration of the same agonist in polycystic ovarian disease subjects and normal control subjects. Serum levels of these hormones were also determined after administration of dexamethasone and adrenocorticotropic hormone (ACTH) as well as bilateral oophorectomy. Subjects with polycystic ovarian disease exhibited significant elevations of serum pregnenolone, 17OH -pregnenolone, and 17OH -progesterone by comparison with normal control subjects. The glandular origins of the excess levels of pregnenolone and 17OH -pregnenolone were more difficult to determine and appear to be different from that of 17OH -progesterone.     

Adjunctive and therapeutic progestins in endometrial cancer

With the arrival of progestin therapy for advanced, metastatic and recurrent endometrial cancer a quarter of a century ago, came the discovery that approximately one-third of all these tumors would show a clinical response. Probably no more than half of this group will survive more than 5 years. Identification of the type of patient who is most likely to respond has proven difficult. Both clinical and histopathological characteristics act only as an unreliable guide. The site of metastasis and the time for a recurrence to appear are the most constant of these factors. It is hoped that the steroid receptor content of the tumor will prove to be as valuable as it has been in the case of breast cancer. At the moment this is under investigation with numerous ongoing studies. Type, dosage and mode of administration of progestin do not appear to be critical factors in tumor response, nor does the type of synthetic agent used. However, medroxyprogesterone has been the subject of numerous symposia and is the best researched. It also offers the opportunity of being administered orally and in large doses. All agents are virtually free of toxic effects and cessation on this basis is unusual. For patients with tumors that either do not respond to progestin, or else have a temporary response, other agents--antiestrogens and cytotoxic--may well prove to be of value either simultaneously or sequentially. These possibilities are under current investigation. The definitive therapy of primary 'nonadvanced' disease is not established and is at this point unproven in any significant published randomized study. Orthodox proven methods of treatment, i.e. surgery and irradiation, must form the initial component in every patient's therapy, whatever the stage of the disease. It is hoped that prospective studies will elucidate the place of progestins in an adjunctive primary setting. However, it must be emphasized that such studies must concentrate on 'high-risk' patients. The probability of proof in any group of 'good prognosis' patients--whatever the numbers entered--appears to be very low.     

The role of new progestins in women''s health

The need for safe and efficacious hormone use underlines the importance of long-term contraceptive options as well as safe short-term hormone replacement when symptoms and clinical judgment dictate this course of action. For contracepting women, new progestins have been introduced in an attempt to provide more effective options with fewer side effects. These have been designed to suit a variety of personal needs and life styles. These agents, found in oral contraceptives, injectables, transdermals, transvaginal rings and intrauterine systems, carry improved risk profiles and a wide range of noncontraceptive benefits. For the post-reproductive woman with a uterus the emphasis is on progestin options with the lowest dose and least systemic side effects. These options must, according to the U.S. FDA, prove not only their efficacy but also their safety. Ongoing studies will be necessary to ensure that menopausal women also enjoy safe hormone use for symptom reduction as well as other possible benefits.     

How progestins prevent endometrial cancer

This article discusses the role of progestational hormones in cancer of the endometrium in menopausal women and indicates the type of progestin and the doses which appear necessary to prevent anomalies of the endometrium. It is in fact established that the incidence of endometrial adenocarcinomas is augmented by the application of a continuous oestrogenic without countervailing progestational-stimulus. Progestogens have an antimitotic action on endometrial cells, which leads to reduction of the oestrogenic stimulus and the probability of the occurrence of tissue anomalies. However, it is probable, and theoretically possible, that the regular disintegration of the endometrium may be capable of removing the potentially anomalous cells before they develop into carcinomas. Any oestrogenic treatment, however, whatever the dose and mode of administration, is not more certain than any other. The association of a progestogen is necessary but the choice of the individual progestogen is dictated by custom or fashion. It seems that administration during 12 days per month in a manner designed to obtain rhythmic bleedings may be the best solution.     

Contraception using normal dose progestins

Contraceptive use of normal dosed progestins continues to be useful for many women who cannot use other contraceptive methods, but appropriate use depends on perfect knowledge of their modes of action, advantages, disadvantages, dosages, and duration of action. Each progestin has its own indications, and contraindications, and not all progestins have contraceptive properties. Most progestins used for contraception are derived from 19 nor-testosterone. Structural modifications of progesterone and testosterone have produced synthetic progestins resistent to hepatic degradation and bioavailable through the oral route. 2 main groups of progestins may be distinguished: androgenic progestins, including the estrone derivatives ethynodiol diacetate and lynestrenol, which have stong antigonadotropic activity and a braking effect on endogenous estrogen secretion, and "pure" progestins derived from 17 OH progesterone, or norpregnanes, such as chlormadinone and promegestone, which have strong luteomimetic activity, no androgenic activity, and weak antiandrogenic activity. Norsteroids administered at normal doses for 21 days/month or in some cases 17 days have a Pearl index of around 1%. This type of contraception requires counting days and taking 1 or 2 pills, and should only be used for women with certain types of problems or hormonal imbalances requiring treatment. Indications may include some cases of uterine polyps, endometrial mucus hyperplasia, uterine fibromas, endometriosis, mastodynies, benign mastopathies, existence of several risk factors for breast cancer, age over 40 years, premenopausal luteal insufficiency, and smoking. Secondary effects, especially metabolic disturbances, may occur and vary according to the formulation, route of administration, and duration of treatment. The 19 nortestosterone progestins commonly used because of their antigonadotropic and antiestrogenic activity have measurable effects on lipid metabolism, apparently in relation to apoproteins A and B, and on glucose metabolism. Some have an effect on the renin substrate, but their role in provoking arterial hypertension appears to be modest. Androgenic effects such as seborrhea and acne may be produced at some dose levels. Medroxyprogesterone acetate, derived from 17 OH progesterone, causes significant metabolic changes including androgenic and hypertensive effects, undesirable effects on glucoregulation, and coagulation effects.     

Clinical profile of contraceptive progestins.

The term progestogen has been widely utilized to indicate the general class of agents that includes both progesterone and its synthetic analogs, whereas the term progestin refers only to synthetic progestational steroids. The development of progestins has been influenced in a major way by the search for orally active hormonal contraceptives, since it is likely that hormonal contraceptives will continue to utilize a progestin, the only possible alternative being represented by the utilization of antiprogestins. Synthetic progestogens in clinical use today belong to three main chemical families: progesterone derivatives (progesterone, retro-progesterone, 19-norprogesterone and 17alpha-hydroxyprogesterone); gonane and 19-nortestosterone derivatives (norethisterone, levonorgestrel, desogestrel, gestodene, norgestimate); a spironolactone derivative. Biological potency of progestogens varies depending on the end-point measured, usually ovulation inhibition and endometrial transformation; with both these tests, the most active compounds are all gonane derivatives, with a potency over a 100 times that of the natural hormone. When administered in adequate doses, a progestin inhibits fertility by inhibiting ovulation. This action is mainly exerted at the hypothalamic level where, physiologically, progesterone decreases the number of LH pulses. When progestogens are delivered directly to the uterine cavity, their action seems to be purely local. It has been amply proven that--even when administered in doses that do not constantly inhibit ovulation--a progestin can still remain effective as a contraceptive by acting at the level of the cervical mucus and, at least in part, of the endometrium. Progestogens utilized today differ largely in their pharmacokinetics. In general, after intake, these compounds are rapidly absorbed and distributed so that peak serum concentrations are reached between 1 and 4 h. Third-generation progestins (desogestrel, gestodene, norgestimate) have common characteristics: a higher affinity for progesterone receptors than their predecessors, a lower affinity for androgen receptors, a higher selectivity of action, a higher central inhibitory activity, a higher potency at the level of the endometrium, and an overall metabolic neutrality, in terms of effects on lipid and carbohydrate metabolism. In general, progestins can induce two types of adverse effects: changes in lipid metabolism and bleeding irregularities. Whereas the newer compounds seem to have overcome the first of these adverse effects, the second remains untouched: to this day, proper cycle control can only be achieved with combined hormonal contraceptives.     

New trends of progestins treatment of endometriosis

The management of endometriosis with OC or progestins is generally safe, effective and well-tolerated and should constitute the first line of medical treatment in symptomatic patients who do not want to have children. Progestins, synthetic progestational agents, have been used in the management of symptomatic endometriosis both as primary therapy and as an adjunct to surgical time. A variety of oral agents have been employed in this regard and investigators have demonstrated differing degrees of benefit. The lack of a standardized instrument to evaluate painful symptoms makes comparative analysis more difficult. Concern about efficacy and side effect has pushed the research on the development of new well-tolerated drugs and to develop new administration routes to minimize general side effects. Aim of the present review is to present the results of clinical studies on new trends of progestins in the treatment of endometriosis.