Selection of patients for clomiphene citrate therapy

Ninety-three infertile women were treated with clomiphene citrate alone or in combination with human chorionic gonadotropin (hCG) for absent or infrequent ovulation. The patients were divided into eight categories according to the diagnosis obtained: ovarian androgenic hyperplasia, adrenal androgenic hyperplasia, mixed ovarian and adrenal androgenic hyperplasia, hypothalamic anovulation, postpill anovulation, follicular phase defect, luteal phase defect, and amenorrhea-galactorrhea syndrome. Each group was analyzed individually to compare the ovulation and conception rates and the complications involved. A survey of the data presented in this study shows that the best response was noted in patients with ovarian androgenic hyperplasia. Patients with a functional pathologic adrenal component responded favorably when dexamethasone was used as an adjuvant to clomiphene therapy. Those with hypothalamic anovulation responded better when hCG was added to clomiphene therapy. Women with postpill anovulation as well as those with follicular phase defect were found to be good candidates for clomiphene therapy. In properly selected patients with poor luteal phase defect, hCG secured excellent results both in ovulation and conception. Patients with lactation amenorrhea failed to ovulate when treated with clomiphene alone.     

Current and future status of ovulation induction in polycystic ovary syndrome

Great progress had been achieved during the last 20 years in the field of ovulation induction in patients with polycystic ovary syndrome (PCOS). Clomiphene citrate remains the first line of treatment for all anovulatory women with PCOS, since in properly selected patients the cumulative pregnancy rate approaches that in normal women. Human urinary gonadotrophins have been used extensively for ovulation induction, but the development of low-dose regimens has opened a new era in the management of anovulation related to PCOS. This article discusses the main advantages and disadvantages of the principal methods and regimens currently used for ovulation induction in patients with PCOS including clomiphene citrate, gonadotrophins, pulsatile gonadotrophin-releasing hormone (GnRH) and GnRH agonists. It also discusses new drugs discovered recently, particularly recombinant gonadotrophins and GnRH antagonists, and provides some thoughts regarding their use in future protocols. Finally, based on the discovery of new ovarian substances which specifically control luteinizing hormone (LH) secretion, this article develops assumptions on possible implications of these substances in the pathophysiology of PCOS and their potential use in the management of the syndrome.     

Successful induction of ovulation in normogonadotrophic clomiphene resistant anovulatory women by combined naltrexone and clomiphene citrate treatment

Patients suffering from normogonadotrophic anovulation and infertility are initially treated with clomiphene citrate. Those who do not respond to clomiphene citrate usually receive gonadotrophin treatment which is labour-intensive, expensive, and associated with an increased risk of multiple pregnancies and ovarian hyperstimulation syndrome. We treated 22 patients with clomiphene resistant normogonadotrophic anovulation with naltrexone (an opioid receptor blocker) alone or naltrexone in combination with an antioestrogen. In 19 patients ovulation and resumption of a regular menstrual cycle was achieved and in 12 out of 19 a singleton pregnancy was observed. In conclusion, ovulation can be induced successfully using naltrexone alone or naltrexone in combination with an anti-oestrogen in clomiphene citrate resistant anovulatory patients. Compared to gonadotrophin induction of ovulation, this method is safe, simple and inexpensive.     

Sequential step-up and step-down dose regimen: an alternative method for ovulation induction with follicle-stimulating hormone in polycystic ovarian syndrome

This study was designed to compare both the effectiveness and safety of two low-dose gonadotrophin regimens (step-up versus sequential step-up and step-down) for ovulation induction in polycystic ovarian syndrome (PCOS) patients. In all, 56 infertile clomiphene citrate-resistant PCOS patients were included in this prospective randomized study. A total of 38 cycles were conducted with a classic step-up protocol, whereas for 35 cycles the follicle-stimulating hormone (FSH) threshold dose was reduced by half when the leading follicle reached 14 mm in diameter (sequential protocol). Serum oestradiol, progesterone and luteinizing hormone concentrations and follicular growth rate were evaluated during the cycle. At the time of human chorionic gonadotrophin administration, cycles treated with sequential protocol exhibited significantly lower oestradiol concentrations [434 +/- 45 versus 593 +/- 67 pg/ml (mean +/- SEM)] and the number of medium-sized (14-15 mm) follicles was significantly reduced (0.3 +/- 0.1 versus 0.8 +/- 0.2) compared with cycles treated with the classic step-up protocol. Moreover, in these cycles serum luteal oestradiol concentrations were decreased significantly (350 +/- 77 versus 657 +/- 104 pg/ ml) compared with the classic step-up protocol. A sequential step-up and step-down protocol seems to be a safe and effective regimen for ovulation induction in PCOS patients. Decreasing the FSH dose following step-up follicular selection may be an alternative method to avoid multifollicular development.     

Variation of dorsal horn cell dendritic spread with map scale

OBJECTIVE: To examine the hypothesis that, in polycystic ovary syndrome (PCOS), ovarian steroids induce adrenal enzyme dysfunction or adrenal androgen hyperresponsiveness to ACTH. DESIGN: Prospective controlled clinical study. SETTING: Reproductive endocrinology unit of an academic medical center. PATIENTS: Twelve women with PCOS who had adrenal androgen excess were compared with five weight-matched ovulatory women. In half of the women with PCOS, prestudy screening was suggestive of mild 3 beta-hydroxysteroid dehydrogenase (HSD) deficiency. INTERVENTIONS: Basal and adrenal dynamic blood sampling before and after GnRH agonist (GnRH-a) administration for 6 months. MAIN OUTCOME MEASURES: Basal E2 and androgen levels as well as dexamethasone-suppressed, ACTH-stimulated 17 alpha-hydroxyprogesterone, 17 alpha-hydroxypregnenolone, and androgen levels before and after ovarian suppression. RESULTS: Although none of the subjects with PCOS proved to have mild 3 beta-HSD deficiency, the majority of them (58%) met the criteria for 17,20 lyase hyperactivity before and after GnRH-a therapy. As a group, the remaining subjects with PCOS exhibited an elevated DHEAS response to ACTH before GnRH-a treatment, which may have normalized after GnRH-a treatment. CONCLUSION: Adrenal androgen excess in PCOS may be heterogeneous in etiology, whereas 17,20 lyase hyperactivity appears to be an intrinsic adrenal disorder, adrenal androgen hyperresponsiveness to ACTH may be ovarian induced. Reliance on historical controls may lead to overdiagnosis of mild 3 beta-HSD deficiency.     

Hypothalamic-pituitary-ovarian response to clomiphene citrate in women with polycystic ovary syndrome

OBJECTIVE: To examine the hypothalamic-pituitary sites of clomiphene citrate (CC) action in women with polycystic ovarian syndrome (PCOS). DESIGN: Prospective controlled trial. PATIENTS, PARTICIPANTS: Seventeen women with PCOS and 9 normal-cycling women. INTERVENTIONS: Subjects with PCOS received CC, 150 mg/d for 5 days. MAIN OUTCOME MEASURES: Follicle-stimulating hormone (FSH) and luteinizing hormone (LH) levels and LH pulse characteristics and their response to gonadotropin-releasing hormone (GnRH, 10 micrograms) were examined before and after 3 days of CC in PCOS subjects during a 12-hour frequent sampling study (n = 8). Daily urinary estrone glucuronide and pregnanediol glucuronide levels after CC were compared with concentrations in normal-cycling women through one menstrual cycle. In another nine PCOS subjects, pituitary and ovarian hormonal cyclicity was monitored by daily blood sampling. RESULTS: Thirteen of 17 treated cycles were ovulatory with normal luteal phases. In the ovulatory cycles, serum LH, FSH, estradiol (E2), and estrone levels increased after CC. Luteinizing hormone pulse frequency was unchanged, but LH pulse amplitude increased significantly after CC. Both LH and FSH response to exogenous GnRH was significantly attenuated after CC treatment. In anovulatory cycles, serum LH, FSH, and E2 increased initially and then returned to baseline and remained unchanged for the ensuring 40 days. CONCLUSIONS: Clomiphene citrate-induced ovulation in women with PCOS is accompanied by increased secretion of LH and FSH with enhanced estrogen secretion. The increased LH pulse amplitude after CC, together with decreased pituitary sensitivity to GnRH, suggests a hypothalamic effect.     

Role of GnRH drive in the pathophysiology of polycystic ovary syndrome

Polycystic ovary syndrome may result from multiple mechanisms, but full expression of the PCO syndrome with hyperandrogenic anovulation depends upon sustained LH drive and relative FSH deficiency. We have described possible intrinsic and extrinsic factors capable of modifying the hypothalamic-pituitary-ovarian axis. Available evidence suggests the presence of an intrinsic alteration in GnRH-LH drive. The long-term natural history of HAA is variable and depends on several factors including obesity, aberrations in insulin action, intrinsic ovarian function, and end-organ responsiveness to androgens. Figure 1 presents a conceptualization of the pathogenesis of PCOS diagramming the multiple modulators of its expression. Long-term suppression of androgens when fertility is not desired should modify the full expression of the PCO syndrome. It is important to appreciate that therapy with oral contraceptive agents has few drawbacks and many immediate and potential long-term benefits for women with HAA. This therapy may be of greatest benefit when started in adolescence prior to the progression of obesity, hirsutism, and thecal-stromal hyperplasia. Women with HAA represent a large subgroup of patients who require individualization of their health care with sensitivity to issues surrounding anovulation, obesity, hirsutism, and infertility.     

Impaired adipocyte lipolysis in nonobese women with the polycystic ovary syndrome: a possible link to insulin resistance?

The polycystic ovary syndrome (PCOS) is the most common hyperandrogenic disorder among women and is characterized by metabolic and cardiovascular aberrations similar to those seen in the so-called insulin resistance syndrome. The regulation of lipolysis was investigated in isolated abdominal sc adipocytes from 10 nonobese women with PCOS and in 11 age- and body mass index-matched healthy women. Eight PCOS women were reinvestigated after 3 months of treatment with combined oral contraceptives containing ethinyl estradiol and norethisterone, which normalized hyperandrogenicity. The PCOS women showed a marked resistance to the lipolytic effect of noradrenaline due to defects at two different levels in the lipolytic cascade: first, a 7-fold reduction in sensitivity to the beta 2-selective agonist terbutaline (P < 0.005), which could be ascribed to a 50% lower beta 2-adrenoceptor density (P < 0.02) as determined with radioligand binding; there was no difference with regard to dobutamine (beta 1) or clonidine (alpha 2-sensitivity) or beta 1-adrenoceptor density; second, the maximum lipolytic response was also 35% lower (P < 0.02) in the PCOS women compared to that in the healthy women. This was seen with all beta-adrenergic agonists and the postreceptor-acting agents forskolin (activating adenylyl cyclase) and dibutyryl cAMP (activating protein kinase). Neither beta 2-adrenoceptor sensitivity or density nor the reduced lipolytic responsiveness was restored by 3 months of oral contraceptives treatment. The results indicate the existence of a marked impairment of catecholamine-induced lipolysis in nonobese PCOS women displaying early features of the insulin resistance syndrome due to multiple lipolysis defects as a lower beta 2-adrenoceptor density and reduced function of the protein kinase, hormone-sensitive lipase complex. These lipolysis defects are identical to those observed in the insulin resistance (metabolic) syndrome and could be a primary pathogenic mechanism for the development of these disorders.     

In vitro fertilization with low-dose clomiphene citrate stimulation in women who respond poorly to superovulation

PURPOSE: Our experience with IVF using low-dose clomiphene citrate for stimulation in "non-" and "poor" responders was reviewed and the treatment outcomes with the previous controlled ovarian stimulation cycles in which hMG and GnRH agonist were used were compared. METHODS: The treatment outcome in 11 non- and 20 poor responders having 30 and 53 clomiphene citrate IVF treatment cycles, respectively, were compared with the treatment outcome in the previous long-protocol buserelin/hMG cycles. RESULTS: The clinical pregnancy rates per oocyte collection achieved in the first clomiphene citrate cycle in non (9.1%)- and poor (10%) responders were comparable to those achieved by poor responders (11.9%) who had buserelin/hMG using the long protocol. Although the numbers were small, a similar pregnancy rate could still be achieved in poor responders up to the third attempt using clomiphene citrate. CONCLUSIONS: IVF using long-protocol buserelin/hMG is more successful than using clomiphene citrate stimulation. However, this advantage may not be significant in those women with a previous poor response to buserelin/hMG. It is suggested that for such poor responders, three attempts of IVF in a clomiphene citrate cycle may offer a viable therapeutic alternative before reverting to more stressful, expensive, and time-consuming treatment.     

Definition and significance of polycystic ovaries

Defining the polycystic ovarian syndrome (PCOS) has challenged clinicians for many years. The clinical, hormonal and morphological definitions of PCOS have their own limitations and do not correspond exactly. Clinically, PCOS can be schematically divided into three components, i.e. hyperandrogenic, anovulatory and dysmetabolic. No one is specific for the syndrome. Hormonally, PCOS has recently been defined by the GnRH agonist test as a functional abnormality in ovarian androgen synthesis. This functional ovarian hyperandrogenism seems closely linked to hyperinsulinism secondary to an insulin resistance. Morphologically, ovarian ultrasonography has emerged in the last decade or so as a new diagnostic tool. However, the sonographic definition of the polycystic ovary (PCO) is controversial, mainly because of a lack of consensus about normative data. The aim of this review is to present the diagnostic dilemma in the diagnosis of PCOS and to discuss the prognostic significance of the PCO.     

Oral contraceptive pills. Prevention of ovarian cancer and other benefits

Each year, about 25,000 new cases of ovarian cancer are diagnosed in the US. Because ovarian cancer has few symptoms in its early stages and there is no effective screening test, most patients have widespread metastases at diagnosis. Epidemiologic studies have demonstrated that OC use can protect against ovarian cancer for at least 15 years after pill use is discontinued. The most likely mechanism of this protective effect is inhibition of ovulation. A strong association between total number of lifetime ovulations and mutation of the p53 gene in ovarian cancers has been reported. Use of the pill for 5 years decreases the risk of ovarian cancer by 40% but decreases lifetime ovulations by only about 15%, suggesting that factors other than prevention of proliferation-associated mutations contribute to the protective effect of ovulation inhibition. The pill also decreases the incidence of endometrial cancer by about 50%. At present, OCs represent the best option for US women from both the contraceptive and cancer prevention perspectives.     

Prediction of the coding sequences of unidentified human genes. VIII. 78 new cDNA clones from brain which code for large proteins in vitro

We investigated the acute effect on the serum levels of ovarian and adrenal sex steroid hormones of the suppression of growth hormone during oral glucose tolerance test (OGTT). A standard 75 g OGTT was performed in 11 healthy women and eight women with polycystic ovary syndrome (PCOS). Another five controls were given a sham loading of oral distilled water. Blood samples were obtained immediately before and at 30-minute intervals after glucose or sham loading. Significant progressive declines in testosterone, estradiol, dehydroepiandrosterone sulfate (DHEAS) and growth hormone levels were observed during OGTT in both groups. In the PCOS and normal groups, respectively, at 120 min, testosterone levels were 75.8% and 64.4% of the baseline (0-time) value, estradiol levels were 83.4% and 83.1%, DHEAS levels were 79.3% and 79.1%, and growth hormone levels were 33.9% and 21.2%. Significant positive correlations were observed between the level of growth hormone and each of the testosterone, estradiol and DHEAS levels in both the groups. The area under the curve for growth hormone was significantly smaller in the PCOS group than in the normal group. Gonadotropins were not changed at any time during OGTT. It appears that growth hormone may modify ovarian and adrenal sex steroidogenic responses to tropic hormones directly or via local insulin-like growth factor-I. Women with PCOS may be relatively deficient in growth hormone, a deficiency which may play a role in the pathophysiology of ovulatory disturbance.     

A clinical retrospective evaluation of FA/HA coated (Biocomp) dental implants. Results after 1 year

The development of ovulation-inducing drugs has enabled clinicians to more effectively treat the hypothalamic, pituitary, and ovarian abnormalities resulting in infertility. Pregnancy rates have been improved with the use of agents such as clomiphene citrate (CC), human menopausal gonadotropin [hMG or follicle-stimulating hormone (FSH) preparations], with gonadotropin-releasing hormone (GnRH) and its analogs, stimulating the development of multiple ovarian follicles and increasing the number of fertilizable oocytes. The use of these drugs is not without certain detrimental or "toxic" consequences. The negative effects from superovulation can occur during follicle development, decreasing the number of healthy oocytes and embryos capable of leading to viable pregnancy. Ovulation induction can lead not only to higher incidences of spontaneous abortions, and multiple and ectopic pregnancies, but also to poor pregnancy rates, due, in part, to asynchrony between embryonic development and the uterine environment. Diseases such as ovarian hyperstimulation syndrome (OHSS), resulting in the secretion of supraphysiologic levels of estradiol, can lend to severe health complications, possibly requiring hospitalization. Most drugs used for ovulation induction can lead to OHSS. Although incidences of OHSS following CC use are less frequent, CC has been associated with hot flushes, multiple gestations, visual disturbances, cervical mucus abnormalities, and luteal phase deficiency. Finally, there are reports that link any or all of the ovulation-inducing drugs with a higher incidence of ovarian and breast cancer, however, a cause-effect relationship has yet to be proven.     

Mid-follicular phase pulses of inhibin B are absent in polycystic ovarian syndrome and are initiated by successful laparoscopic ovarian diathermy: a possible mechanism regulating emergence of the dominant follicle

The hypothalamic pulse generator of GnRH is recognized to be central to ovulatory function as evidenced by the anovulation of women with hypogonadotrophic hypogonadism due to Kallmann's syndrome or severe anorexia nervosa. LH is released from the anterior pituitary in pulses, the frequency of which is closely entrained with those of GnRH. In contrast, secretion of FSH is influenced by a number of regulatory molecules, including GnRH, estradiol, inhibin, and activin. The close temporal relationship between changes in levels of inhibin B and FSH in the mid-follicular phase suggests that the release of inhibin B by the preovulatory follicle critically regulates pituitary FSH secretion. Polycystic ovarian syndrome (PCOS) is one of the most common endocrine disorders affecting ovulation, and abnormal ovarian morphology as detected by ultrasonography remains the most sensitive diagnostic marker for this disorder. The etiology of PCOS is unclear, but its effective treatment by both anti-estrogens and by exogenous FSH suggests that a primary disorder of FSH regulation may be central. To investigate the possible role of inhibin B in the pathology of PCOS, serum inhibin B levels were measured in 10 women with PCOS on cycle day 5 of a spontaneous or progestrogen-provoked bleed and compared with levels on cycle day 5 of 10 women with regular ovulatory cycles. The mean serum inhibin B levels in the PCOS patients were significantly higher at 248 (+/- 43.4) pg/mL compared with normal controls, 126 (+/- 18.6) pg/mL (P < 0.01). Ten women with clomiphene resistant PCOS and 5 normal controls consented to undergo serial blood sampling on cycle day 5. Time Series Analysis using a Fourier Transformation to analyze the power spectrum of the data revealed that in normal women there is a distinct periodicity in inhibin B levels with a clear peak detectable every 60-70 min (P < 0.05), whereas in women with ovulatory dysfunction due to PCOS, no such pattern of regular pulsatility was seen. Four women with PCOS whose anovulation was successfully treated with laparoscopic ovarian diathermy (LOD) underwent repeat venous sampling following LOD. Their serum inhibin B levels fell to the upper limit of the normal range (160 +/- 38.5) pg/mL, and pulsatility was initiated. It is possible that inhibin B pulses are being generated directly by the ovary in response to pulses of GnRH in the peripheral circulation, or indirectly in response to FSH pulses arising in the pituitary. The function of inhibin B pulses in the mid-follicular phase of the normal cycle remains to be elucidated, but the absence of the normal pulsatile pattern in women with PCOS, in conjunction with high basal levels of inhibin B arising from the multiple small follicles characteristic of the PCOS ovary, appears to reinforce the development of a large cohort of small, developmentally arrested, and ultimately atretic follicles in these patients. Initiation of normal inhibin B pulsatility by LOD in patients with polycystic ovaries appears to correlate with the post-operative onset of ovular cycles.     

FFI cases from the United States, Australia, and Japan

In this study we examined the possible correlation between insulin metabolism and outcome of gonadotrophin stimulation in infertile clomiphene citrate resistant women with polycystic ovary syndrome (PCOS). The patient group comprised 42 women who were entered into the study in a consecutive fashion. Following performance of the CIGMA (continuous infusion of glucose with model assessment) test, 17 women were classified as insulin resistant and 25 women as non-insulin resistant. Each woman received up to two cycles of low-dose follicle stimulating hormone (FSH) stimulation starting with 75 IU of FSH for 1 week, giving a total of 70 cycles performed. The insulin resistant PCOS women required more gonadotrophin and a longer time to achieve follicular maturation. By multiple regression gonadotrophin consumption correlated best with CIGMA value but not with fasting insulin concentration or body mass index. In the insulin resistant PCOS women 10 out of 29 cycles were cancelled due to a multifollicular response, while only one of 41 cycles was cancelled in the non-insulin resistant PCOS women. Although ovulation rate in completed cycles was similar between the groups, the conception rate was significantly better in the non-insulin resistant PCOS women. In conclusion, in PCOS women insulin resistance seems to be an unfavourable condition resulting in an elevated cancellation rate and a low conception rate following low-dose FSH stimulation.     

The results of an in vitro fertilization program: two regimens of superovulation

Gonadotropin-releasing hormone (GnRH) agonists are increasingly used in ovarian hyperstimulation protocols in in vitro fertilization (IVF) programs. From March 1992 to June 1993, 565 patients attending our Institute underwent superovulation in 1104 IVF program cycles. Of these cycles, 650 were stimulated with clomiphene citrate and gonadotropins (human menopausal gonadotropin/hMG), and 454 with the GnRH agonist buserelin and hMG in a group of patients who had earlier failed to respond or did not conceive after clomiphene citrate/hMG stimulation. The ovarian response was similar in both groups, however, with the use of buserelin more oocytes were recovered -4.9 +/- 3.2 and 3.5 +/- 2.3 oocytes, respectively. The clinical pregnancy rate per transfer in the group of patients superovulated with buserelin/hMG was twice that of the clomiphene citrate/hMG group (21.0% vs. 10.4%). The relatively high pregnancy rate with the buserelin/hMG regimen in the group of 'poor responders' may be connected with GnRH agonist-induced pharmacological hypophysectomy and the sequelae thereof: normalization of some endocrinopathies, absence of an endogenous luteinizing hormone (LH) surge and better endometrium receptivity, oocytes and embryo quality.     

Combined intra-uterine and extra-uterine pregnancy associated with mild hyperstimulation syndrome after clomiphene ovulation induction

We report a combined intra-uterine and tubal pregnancy associated with mild ovarian hyperstimulation syndrome (OHSS) following ovulation induction by clomiphene. The diagnosis of ectopic pregnancy was originally missed until rupture occurred. OHSS confused the clinical picture, the important diagnostic feature being the fall in the haemoglobin concentration. The patient had a left partial salpingectomy and the uterine pregnancy progresses normally.     

Current concepts of polycystic ovary syndrome

Polycystic ovary syndrome (PCOS) may be loosely defined as unexplained hyperandrogenism, with variable degrees of cutaneous symptoms, anovulatory symptoms, and obesity. The vast majority of patients with the full-blown Stein-Leventhal syndrome have functional ovarian hyperandrogenism (FOH). However, FOH often occurs without the LH excess or polycystic ovaries of classic PCOS. Functional adrenal hyperandrogenism (FAH) is often found in the syndrome, but it is less closely associated with anovulatory symptoms than is FOH. The vast majority of FOH seems to arise from abnormal regulation (dysregulation) of ovarian androgen secretion. This typically is due to escape from desensitization to luteinizing hormone (LH); this appears to occur because of a breakdown in the processes that normally coordinate ovarian androgen and oestrogen secretion so as to prevent hyperoestrogenism. Similar dysregulation of adrenal androgen secretion in response to ACTH seems to account for most FAH. Dysregulation of androgen secretion may affect the ovary alone (isolated FOH), the adrenal alone (isolated FAH), or both together. Modest insulin resistance is common in PCOS/FOH, and the resultant hyperinsulinaemia is a major candidate as the cause of the dysregulation. The hyperinsulinaemia may arise from either 'nature' (genetic defects) or 'nurture' (exogenous obesity). Although hyperinsulinaemia alone does not have an obvious effect on steroidogenesis, it may act in genetically predisposed women as a 'second hit' to unmask latent abnormalities in steroidogenesis. The ovary, the adrenal cortex, and several other organs paradoxically function as if responding to the hyperinsulinaemic state in spite of resistance to the effects of insulin on glucose metabolism. PCOS should be viewed as an early manifestation of a hyperinsulinaemic condition that will predispose to cardiovascular and metabolic complications later in life. A subset of PCOS patients appear to have not only insulin resistance but also beta-cell secretory dysfunction, which may indicate a relationship of the disorder to NIDDM. The fundamental genetic defects remain to be elucidated.     

Evaluation and treatment of low responders

Identification and treatment of low responders to ovulation induction is one of the most frustrating challenges in reproductive medicine. Because complex ovulation induction is required so frequently and is so expensive, efficient diagnosis of hyporesponders is critical. At present, the best techniques of evaluating ovarian reserve are basal follicle-stimulating hormone/Estradiol levels early in the proliferative phase and the clomiphene citrate challenge test. When poor responders are identified, strong consideration should be given to adjunctive approaches such as gonadotropin-releasing hormone analog and microdose flare or possibly, embryo hatching in those women undergoing in vitro fertilization.     

Attitudes to current oral contraceptive use and future developments: the women's perspective

OBJECTIVES: The study was planned to determine current trends in contraceptive usage and to examine the attitudes, needs and preferences of women with respect to oral contraceptives. METHODS: Semi-structured interviews were carried out with women (n = 1201, aged 16-45 years) in Germany, the UK and France. RESULTS: The study revealed that oral contraceptives were the most popular method of contraception employed, followed by condoms, and that the majority of respondents were aged 16-19 years when they first used an oral contraceptive. An important finding of the study was that an oral contraceptive was first used only after having sexual intercourse for the first time (within 1 year), emphasizing the importance of effective contraceptive information and education for adolescents. Regarding non-contraceptive health benefits, protection from ovarian and endometrial cancer was perceived by respondents to be of the greatest importance; however, few women were spontaneously aware of this benefit. When given a number of different oral contraceptive intake options to assess, the established 'once daily for 21 consecutive days' option remained the most popular, although a 'once weekly' alternative was cited by many women. When asked about the preferred frequency of menstrual bleeding, there was a polarization between women favoring the normal monthly bleed and those wanting a 'no-bleed' regimen. CONCLUSION: Women are poorly informed about oral contraceptive use, and are largely unaware of the important long-term non-contraceptive benefits. Many women would prefer alternative pill intake options and a significant number would favor a 'no-bleed' regimen.