Poor responders in IVF: an update in therapy.

INTRODUCTION: Assisted reproduction techniques are the frequent treatment of infertility. Despite the advances in science and technology, the management of poor responder patients is still considered as one of the most urgent problems. The lack of unified definition makes the management of the poor responder patients very difficult. The aim of this review is to examine and compare the different studies done about the problem of poor responder patients. METHODS: On an online research of MEDLINE/PUBMED, we found several studies on pharmacological treatment for poor responders' patients. RESULTS: Our review shows that in the years numerous therapies for the management of these patients who do not respond to ovarian stimulation have been evaluated and studied, but the main problem is the large and still not well-defined meaning of poor responder women. CONCLUSION: The management of the poor responder patients is very difficult. Currently, there is no any standard treatment for poor responder patients. Considering the importance of the problem, it is important to identify a diagnostic and therapeutic target. Our review shows that there are many studies with different therapeutic approaches which deserve further in-depth study to standardize diagnostic and therapeutic target.

Long acting contraceptives. Present status.

Long acting injectable hormonal contraceptives are among the most effective fertility regulating agents developed; yet they are also among the most controversial because of animal data indicating a possible carcinogenic potential in several species. A critical analysis of these animal findings has revealed, in all instances, the existence of specific mechanisms not occurring in the human. For this reason, most national and international scientific bodies who have reviewed this issue have concluded that there are no toxicological reasons for not using long acting hormonal contraceptives. Long acting agents can be divided into 2 separate groups: those having a duration of action of one month, which are composed of a long acting oestrogen and a progestagen, and those lasting for several months which consist of only a progestagen. Among the injectable progestagen-only contraceptives tested, only 2 have so far reached the international market: depot medroxyprogesterone acetate (DMPA), which has been administered at 3- or 6-month intervals and norethisterone enanthate, which has been injected at intervals ranging between 2 and 3 months. The most important side effect observed with these 2 agents is a complete disruption of the menstrual bleeding pattern, leading - in some cases - to total amenorrhoea, which is more frequent with depot medroxyprogesterone acetate than with norethisterone enanthate. The latter, however, has a shorter duration of action with a higher pregnancy rate than the former. Other adverse reactions are rare and of no real importance. Metabolic effects with progestagen-only injectable preparations are, in general, mild and less marked than with combined oestrogen-progestagen formulations. Recent investigations have shown that the return of fertility following their use is delayed but in no way impaired. Monthly injectable oestrogen-progestagen combinations have been tested to a more limited extent and these agents are available only in a very few countries. Their main advantage over progestagen-only preparations is that they allow a reasonable menstrual bleeding pattern in the majority of cases. Their obvious disadvantage is that they contain a long acting oestrogen.

Comparative clinical evaluation of the effect on carbohydrate and lipid metabolism of two norethisterone-containing hormonal contraceptives: Mesigyna and TriNovum.

The effect on carbohydrate and lipid metabolism of two hormonal contraceptive preparations containing norethisterone (commercially known as Mesigyna and TriNovum) was studied in a total of 60 women, before and after 6 months of treatment. Carbohydrate metabolism was evaluated by means of a euglycemic glucose clamp test; lipid metabolism was monitored by measuring total cholesterol, HDL-cholesterol, LDL-cholesterol, VLDL-cholesterol, and triglycerides. The two groups were properly matched with the exception of pretreatment levels of cholesterol and LDL-cholesterol. At the end of treatment, no difference was found within or between groups in fasting glucose and insulin levels and in glucose rate of disappearance. A significant increase in total cholesterol, HDL-cholesterol, and VLDL-cholesterol was found in both groups at the end of the treatment period; in addition, TriNovum caused a significant increase also in triglycerides. In conclusion, the safety of both preparations with regard to carbohydrate metabolism was confirmed using the most accurate method available; furthermore, changes in lipid metabolism were such as to have little clinical significance.

Sequential Gn-RH superagonist and medroxyprogesterone acetate treatment of uterine leiomyomata.

A group of 48 women with symptomatic leiomyomata were treated during 6 months with the short-acting Gn-RH superagonist analog buserelin. The first (group C) was followed up for an additional six months of no medication. The second (group M) was treated for 6 additional months with medroxyprogesterone acetate (MPA) at doses decreasing from 200 to 25 mg/day. Buserelin therapy significantly decreased uterine size (P less than 0.001) in all patients, the average final volume being 48.5% of the original (from 262 +/- 147 ml to 127 +/- 85.4 ml). In group C there was a significant (P less than 0.001) re-growth during the post-treatment observation period (from 120 +/- 81.0 ml to 198 +/- 77.2 ml); a significant (P less than 0.01) re-growth was also observed in group M during MPA medication (from 132 +/- 77.2 ml to 170 +/- 96.0 ml). The agonist had also a marked effect on fibroids: on average they decreased from 75.1 +/- 74.3 ml to 24.7 +/- 23.3 ml (P less than 0.025). In group C during the post-buserelin period of observation without treatment, there was a significant re-growth from 23.7 +/- 21.6 ml to 47.7 +/- 27.5 ml (P less than 0.001), whereas in group M treatment with MPA prevented any significant re-growth (from 25.6 +/- 24.8 to 30.6 +/- 32.9 ml; P greater than 0.3).

[Causes for transfer of obstetric patients to an intensive care unit (1990-19960]. / Cause di trasferimento di pazienti ostetriche ad un centro di rianimazione (anni 1990-1996).

BACKGROUND: In order to have an updated review of the causes for transferring patients from our Institute to Intensive Care Unit (ICU), a study has been conducted on patients admitted from 1990 to 1996. METHODS: Of the 28 women transferred, one underwent dilatation & curettage of uterine cavity after abortion, 3 had a normal delivery and 24 underwent a cesarean section. RESULTS AND CONCLUSIONS: The complications were as follows: respiratory failure (5 cases); suspected or confirmed lung embolism (1); cerebral ischemia (1); septic complications (1); cardiocirculatory complications (19 cases; 7 of them were due to DIC; 6 due to cardiocirculatory failure; 6 due to haemorrhagic shock). These patients were divided into 3 groups, those with pre-existing pathologies which worsened (2 cases); those due to deterioration of pathology arose during pregnancy (17) and, finally, complications during delivery (9). In total the cases of mortality were 7, all of them following cardiocirculatory complications.

[Contraception and voluntary termination of pregnancy. Survey of a sample of 500 women]. / Contraccezione e interruzione volontaria della gravidanza. Indagine conoscitiva su di un campione di 500 donne.

In order to better evaluate the link between contraceptive attitudes and induced abortion, 500 women who underwent voluntary termination of pregnancy (VTP) at the First Institute of Obstetrics and Gynaecology of the University of Rome "La Sapienza" were interviewed. They were young (median age 28 years), medium to high educated (61%), non married (52.4%), nulliparous (59.2%) women. Forty-two percent of them had the first sexual intercourse before 18 years of age and 72.6% at least five years before. Ninety-five women (19%) admitted a previous voluntary termination of pregnancy. Withdrawal (305 women), oral contraceptives (246 women) and condom (223 women) were the most widely used methods of fertility regulation, but the pill had been taken only for short periods of time, never exceeding one year. Withdrawal resulted to be the most utilized method during the cycle in which conception occurred (49.4%); no method had been employed by 34.8% of the women. The diffusion of modern methods of fertility regulation greatly influences the number of induced abortions in Italy, as clearly indicated by the progressive reduction of VIP starting from 1982 paralleled by a constant increase in OCs diffusion. Our data, although limited in number, confirm that induced abortion is the consequence of an insufficient use of modern methods of fertility regulation.

[Preoperative treatment with GnRH analogs in hysterectomy]. / Trattamento preoperatorio con analoghi del GnRH nella isterectomia.

The authors discuss the usefulness of GnRH analogues inducing, through pituitary desensitization, a transient block of gonadal steroidogenesis--before hysterectomy for uterine leiomyomas. In patients with severe anemia these drugs proved to be very effective in improving the haematologic parameters; they also cause a significant reduction of uterine volume, thus allowing, in selected cases, vaginal hysterectomy in selected cases.

[Clinical use of progestins]. / L'impiego clinico dei progestinici.

The development of progestogens from the thirties till now and their main clinical uses are considered. Progestogens play an essential role not only in the treatment of dysfunctional uterine bleeding and endometrial carcinoma, but also in oral contraception and in hormone replacement therapy for menopausal women. In the last two cases the attention is focused on the relationship between the use of progestogens and the risk of mammary carcinoma.

[Pharmacological preparation of the endometrium in surgical hysteroscopy]. / La preparazione farmacologica dell'endometrio nell'isteroscopia operativa.

Danazol, GnRH analogues (GnRH-A), progestins and gestrinone have been indicated for medical pre-treatment of surgical hysteroscopy, although only danazol and GnRH-A had some clinical evaluation. Pre-hysteroscopic pharmacological preparation is, in general, intended to reduce endometrial thickness, intraoperative bleeding and the need for endouterine distension with fluid media. In addition, in case of endometrial ablation, medical pre-treatment should facilitate the complete removal of endometrium, thus allowing better long-term results. The mechanism of action of progestins, danazol and gestrinone is partly indirect, through inhibition of ovulation and mild reduction in the synthesis of gonadotropins, and partly direct, through, first, decidualization of the endometrium, and then complete inactivation. On the other hand, GnRH-A have only an indirect, central mechanism of action of inhibition, through pituitary desensitization, of the synthesis of gonadotropins, thus inducing a profound hypoestrogenism. GnRH analogues appear to be more effective and rapid than danazol at the endometrial level and better tolerated. However, the effectiveness of pre-treatment versus no treatment needs to be clearly demonstrated in well-designed controlled studies. No significant difference, so far, has been found between danazol and GnRH analogues in terms of both surgical safety and long-term results.

Safety of modern oral contraception: the options for women: lessons to be learned.

The relatively short history of hormonal contraception has been marked by a series of 'pill scares', all of which--after creating panic among users--were proven to be unfounded in terms of public health impact. The latest pill scare, provoked by regulatory action in the United Kingdom and the Federal Republic of Germany in response to the publication of a series of articles indicating a doubling of risk of deep venous thrombosis in users of oral contraceptives containing third-generation progestins, seems finally settled: both the British and the German Drug Regulatory Authorities have now reverted their verdict. The damage unfortunately stays: hundreds of thousands of women have been compelled to abandon the pill of their choice, often deciding to drop contraception altogether, thereby exposing themselves to unwanted pregnancy and--in a number of cases--to pregnancy termination. This latest episode should be turned into something positive: we need to learn that, in the case of drugs in widespread use, before restrictive action is taken--and except for very rare and specific instances--the scientific community must carry out an exhaustive debate on the reality and importance of the observed effects. Although the public should, in each instance, be properly informed, it is only after this process has been completed that restrictive action should be taken. It is hoped that, after this last episode, all concerned have learned this simple principle and will accept being guided by it from now on.

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.

The endometrium and hormonal contraceptives.

Contraceptive progestogens have a series of effects on the endometrium that depend on the existence of oestrogen priming and therefore on the time of administration, the route through which the hormone is released to the body (systemic or locally in utero) and the available daily dose. The effects of a contraceptive progestogen can be divided into two main categories: changes in the endometrial structure and vascularization and alterations of the menstrual bleeding pattern. Whereas orally administered progestogens usually cause endometrial decidualization and an important stromal reaction, the i.m., or local, intrauterine delivery is more apt to cause atrophia. Finally, all progestogens, when given alone at contraceptive doses (and irrespective of their mechanism of action), cause some disruption of menstrual bleeding patterns. This is maximal with injectable, long-acting progestogens, such as depot-medroxyprogesterone acetate and norethisterone enantate.