Walter Vegetti

Reliability of ovulation tests in infertile women

Objective To assess the reliability of the most widely used clinical methods for predicting or confirming ovulation. Methods We monitored spontaneous cycles in 101 infertile women using basal body temperature (BBT), transvaginal ultrasound, a urinary stick system for LH surge, and three serum progesterone measurements in the midluteal phase. Transvaginal ultrasound monitoring was standard for ovulation detection and sensitivity. We calculated specificity and accuracy of each method compared with that standard. Results Follicular development and ultrasound evidence of ovulation were confirmed in 97 of 101 cycles (96%). Urinary LH surge preceded follicular rupture assessed by ultrasonography in all cycles and showed concordance with ultrasound-evidenced ovulation in 98 of 101 cases. The timing of BBT nadir had wide variability, and BBT and ultrasonography agreed in a similar percentage of cases (74%). Midluteal serum progesterone assessments showed ovulatory values in 93 subjects, and ovulation was concordant with ultrasonography in 90 subjects. Conclusion Urinary LH was accurate in predicting ovulation with ultrasonography as the standard for detection, but time varied widely. The nadir of BBT predicted ovulation poorly. The BBT chart was less accurate for confirming ovulation, whereas a single serum progesterone assessment in midluteal phase seemed as effective as repeated serum progesterone measures.

PREMATURE OVARIAN FAILURE

Secondary amenorrhoea with elevated gonadotrophins occurring under the age of 40 (premature ovarian failure (POF)), and at the age between 41 and 44 years (early menopause (EM)), respectively, affects 1-2% and 5% of women in the general population. Objective of this study was to evaluate the prevalence of familial cases of POF and EM and to assess the clinical and genetic characteristics of these patients. One hundred and sixty women with idiopathic secondary amenorrhoea before the age of 45 and serum follicle-stimulating hormone (FSH) levels greater than or equal to 40 IU/l were included in the study. Tests performed on patients included complete medical history, pedigrees analysis, clinical pelvic examination, gonadotrophins and thyroid assessment, chromosomal analysis. The 160 patients included in the study showed idiopathic POF (n=130) or EM (n=30). Following pedigree assessment, we were able to identify an incidence of familial cases of 28.5% in the POF group (n=37) and of 50% in the EM group (n=15). POF and EM condition were often present in the same family. There were no differences between POF and EM patients and between familial and sporadic cases regarding age at menarche, personal history, gynaecological history, weight, height and diet habits. There was a statistically significant difference between sporadic and familial cases in age at POF onset: 32.0+/-7.3 years (12-40) compared to 35. 0+/-5.8 (18-40), respectively (P<0.05). The POF and EM families identified showed two or more affected females and transmission through either maternal or paternal relatives; in four families both maternal and paternal transmission was observed. This study suggests that idiopathic POF and EM conditions, differing only in age of menopause onset, may represent a variable expression of the same genetic disease. The different age of menopause onset in these patients may be explained by genetic heterogeneity and/or by different environmental factors. Our results indicate a high rate of familial transmission of the condition. Pedigrees analysis suggests an autosomal or an X-linked dominant sex-limited pattern of inheritance for POF and EM.

Two-year treatment with oral contraceptives in hyperprolactinemic patients.

The aim of this prospective study was the follow-up for 2 years in symptoms, serum prolactin (PRL) levels, and radiological aspects of a group of young patients using oral contraceptives (OC) with hyperprolactinemia. A total of 16 hyperprolactinemic women (eight with idiopathic hyperprolactinemia and eight with pituitary microadenoma) who started OC use were admitted in the study. After 2 years of OC use, the assessable patients showed a nonsignificant decrease in plasma PRL level (26.8 +/- 29.4 micrograms/mL, range 4.2-97.1 micrograms/mL vs 56.3 +/- 31.5 micrograms/mL, range 23.5-144 micrograms/mL). No patient experienced any radiological changes during OC treatment. In conclusion, although the number of observations is limited, the data suggest that after 2 years of follow-up, no harmful effect of OC use was observed in these patients.

Effectiveness of Sonohysterography in Infertile Patient Work-Up: A Comparison with Transvaginal Ultrasonography and Hysteroscopy

Objective: The aim of this comparative study was to evaluate the accuracy of transvaginal ultrasonography (TVU), sonohysterography (SHG) with sterile saline solution compared to hysteroscopy in the diagnosis of intrauterine pathology in a population of infertile patients before an in vitro fertilization (IVF) program. Patients/Methods: 98 infertile patients with a mean age of 33.9 years (range 27–41) underwent TVU assessment and SHG with sterile saline solution immediately followed by hysteroscopy. Results: The clinical findings obtained by TVU, SHG and hysteroscopy were compared. Sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of TVU and SHG compared to hysteroscopy were calculated. The TVU sensitivity and specificity compared with hysteroscopy were 91 and 83% respectively. Using TVU, a 9.2% false positive rate (9 cases) and a 5.1% false negative rate (5 cases) were detected compared to hysteroscopy. The TVU PPV and NPV were 85.4 and 90% respectively. SHG yielded better results: sensitivity and specificity when compared to hysteroscopy were 98 and 94% respectively. The SHG PPV and NPV were 95 and 98% respectively. Accuracy of SHG was significantly better than TVU considering all intrauterine pathologies and polyps. Conclusion: In experienced hands, SHG is an easy, safe, and well-tolerated alternative to diagnostic hysteroscopy in the initial evaluation of uterine cavity infertile patients.

Ovarian activity during regular oral contraceptive use

The aim of this study was to assess whether during regular OC use ovarian activity might lead to ovulation, as assessed by ultrasound (US) evaluation of follicular growth and blood levels of 17-beta-estradiol and progesterone. A total of 51 healthy women with normal menstrual cycles (28 +/- 3 days) and no gynecological symptoms were recruited. A total of 22 patients were given a triphasic OC pill containing 35 mg ethinyl estradiol (EE) and 50 mg desogestrel (DSG) in the first seven tablets; 30 mg EE and 100 mg DSG in tablets 8 to 14, and 30 mg EE and 150 mg DSG in tablets 15 to 21; 29 patients received one of two OC pills, both containing 20 mg EE plus 150 mg DSG (15 patients) or 75 mg of gestodene (14 patients). A total of 86 cycles were monitored: 51 during the 3rd-4th cycle and 35 during the 6th-8th cycle of OC treatment. Follicular-like structures were observed in nine patients. The frequency of follicular-like structures was similar during the 3rd-4th cycle (9%) and during the 6th-8th cycle (11%). There was no relationship between follicular growth and blood levels of E2 and progesterone, which always appeared suppressed. In conclusion, the results of this study suggest that during OC use (even with low dose of ethinyl estradiol), a little ovarian activity may be present without ovulation.

Fsh and folliculogenesis : from physiology to ovarian stimulation

FSH is a glycoprotein hormone consisting of two peptide subunits. The role of FSH in folliculogenesis is well known: to stimulate the formation of a large pre-ovulatory follicle that, because of its FSH-dependent maturation, is capable of ovulation and forming a corpus luteum in response to the mid-cycle surge of LH. FSH is widely used in ovarian stimulation for assisted reproduction techniques. Ovarian stimulation protocols combine the use of human menopausal gonadotrophin, urinary FSH or recombinant FSH with gonadotrophin-releasing hormone (GnRH) agonists or antagonists in order to increase oocyte number and to avoid premature LH surge. Recently, the availability of recombinant LH has permitted new stimulation protocols, combining recombinant FSH, recombinant LH and GnRH antagonists. Due to the limitations of the new Italian law in terms of the number of oocytes that can be fertilized, protocols with a softer ovarian stimulation are now considered, reducing risk of ovarian hyperstimulation syndrome, multiple pregnancies and emotional and physical burdens on the patients. Long-acting FSH preparations are also under clinical study. Knowledge of the stereochemical three-dimensional structure of FSH and its receptor will allow the study of new non-peptide orally administered molecules that fit the FSH receptors.

A practical guide to the diagnosis and management of amenorrhoea.

SummaryFor women of reproductive age, pregnancy and lactation are the two most common physiological causes of amenorrhoea. This article concentrates on pathological causes of amenorrhoea. Primary amenorrhoea refers to the absence of menarche at the age of 16 and secondary amenorrhoea is the cessation of menses for at least 6 months in already cycling women.Amenorrhoea is not a diagnosis but a symptom indicating anatomical, genetic and neuroendocrine abnormalities. It can be determined by two different groups of causes: (a) anatomical defects of the genital organs; (b) endocrine dysfunctions.Both congenital and acquired anomalies in the structure of the uterus and vagina could produce amenorrhoea; nevertheless, in the vast majority of patients, amenorrhoea is related to an ovarian malfunction. Diagnostic work-up includes history, physical examination, laboratory data and imaging.Amenorrhoea resulting from ovarian malfunction is associated with 4 distinct endocrine conditions. Hyperprolactinaemic amenorrhoea is often associated with a pituitary adenoma. Prolactin-lowering drugs, cyclical progestogen and hormone replacement therapy (HRT) are the different choices of treatment for cycle disturbance; a contraceptive pill can be used to ensure contraception, while prolactin-lowering drugs induce fertility in patients who desire pregnancy.Hypogonadotrophic amenorrhoea is frequently associated with stress and nutritional deficiency. If this is the case the patient should simply be counselled. A sequential use of estrogen and progestogen can be suggested to prevent estrogen deficiency or for psychological reasons. If contraception is needed, oral contraception may be the choice for both cycle and fertility control. If the patient desires pregnancy, ovulation may be induced with pulsatile gonadotrophin-releasing hormone (GnRH) in patients with hypothalamic disfunction and with gonadotrophins in patients with pituitary failure.Hypergonadotrophic amenorrhoea is the result of an ovarian failure. There is no curative therapy for these amenorrhoeas. However, a long term hypoestrogenic condition should be treated with estrogen to cure symptoms and to prevent an increased risk of cardiovascular disease and osteoporosis.Normogonadotrophic amenorrhoea is caused by some disturbance in the pattern of pulsatile GnRH secretion. Since these women have some ovarian activity, they are not hypoestrogenic and will bleed in response to progestogen withdrawal. Most of these patients are likely to have polycystic ovarian disease (PCO). Menstrual bleeding can be induced in these women by cyclical progestogen administration or the sequential use of estrogen plus progestogen. Oral contraception is indicated not only in patients who desire to be protected against pregnancy but also in women with acne and hirsutism. These frequently present signs of hyperandrogenism are consistently improved by the ovarian suppression induced by the contraceptive pill. The beneficial effect of the pill can be reinforced by the simultaneous use of antiandrogens. Women with normogonadotrophic amenorrhoea and desiring pregnancy have a less favourable response to all forms of ovulation induction (antiestrogen, GnRH and gonadotrophin preparations).

Case-Control Study on Risk Factors for Premature Ovarian Failure

Objective of this case-control study was to investigate the potential risk factors for premature ovarian failure (POF). Seventy-three patients with secondary hypergonadotropic amenorrhea and, as control group, 144 women with acute, non-gynecological, non-neoplastic, non-hormone-related diseases were included in the study. Information was obtained on sociodemographic characteristics, gynecological and obstetric data, general lifestile habits, smoking habits and history of selected gynecological and other clinical conditions. A statistically significant association between high education level and POF was found (p = 0.03). Parity was related to a reduced risk of POF and this reduction increased with the number of live births (p = 0.02). No association emerged between POF risk and age at menarche, cycle length and oral contraceptive use. Women with POF could not be distinguished from control women by behavioral and reproductive history, except for lower fertility. The minor influence that reproductive and lifestyle factors have on the occurrence of POF suggests that genetic inheritance plays a more important role.

An Open Randomized Comparative Study of an Oral Contraceptive Containing Ethinyl Estradiol and Cyproterone Acetate with and without the GnRH Analogue Goserelin in the Long-Term Treatment of Hirsutism

A multicenter randomized study was carried out to compare the efficacy of combined therapy with a GnRH analog (goserelin) + an oral contraceptive (OC) containing ethinyl estradiol and cyproterone acetate and same OC alone in the treatment of severe hirsutism. The effect of these two therapies was assessed in a subjective and an objective evaluation of hair growth. According to the subjective evaluation, judged by physician and patient. 95% of patients obtained a partial response. The objective response was assessed by measuring the mean diameter of hair from 3 different areas and 1 control area. The decrease in hair diameter compared to pretreatment was statistically significant for both treatments, mainly for the abdomen and face. The difference between the two groups did not reach statistical significance. Therefore, we assume that OC alone remains the treatment of choice for hirsutism. However, the addition of the GnRH analog to OC needs further investigation and could be justified for patients with no response to standard monotherapy.

Endometrial morphology and ultrasound vascular findings. A randomized trial after intramuscular and vaginal progesterone supplementation in IVF.

Luteal-phase supplementation has proved necessary in Gn-RH analog and human gonadotropin-stimulated cycles. We studied the effects of vaginally and intramuscularly delivered progesterone on the endometrium. Thirty patients enrolled in an IVF program without embryo transfer due to absence of fertilization were included in the study. Patients were randomly allocated to two treatment groups. Group A (n = 15) was administered 200 mg progesterone b.i.d. by the vaginal route (Esolut, Angelini) starting on the day of oocyte pick up and group B (n = 15) was given 100 mg intramuscular progesterone once daily (Prontogest, Amsa). Six days after HCG administration, biopsies were obtained for endometrial histological maturation and estrogen (ER) and progesterone (PR) receptor analyses. In addition, ultrasound measurements of endometrial thickness were made and uterine and myometrial artery flow was determined. Serum concentrations of estriol and progesterone were measured on the day of HCG, at oocyte pick up and at endometrial biopsy. The two treatment groups were similar in terms of follicular phase parameters during superovulation with Gn-RH analog and gonadotropin. Histologic, receptor and ultrasonographic analyses showed no significant differences between the two treatment groups. Our results indicate that both intramuscular and vaginal progesterone are equally effective on the endometrium.