High fecundity rates in donor oocyte recipients and in-vitro fertilization surrogates using parenteral oestradiol valerate.

Ovum donation and in-vitro fertilization (IVF) surrogacy can help couples with difficult infertility problems achieve pregnancy. Most centres using oral oestrogens and oestradiol patches report pregnancy rates in the range of 30% per cycle. Parenteral oestradiol valerate has pharmacological properties that make it an attractive option for preparing the endometrium in the recipients undergoing these procedures. When the egg providers were under age 35 years, and using oestradiol valerate in the recipients, we achieved a 61% clinical pregnancy rate in 62 cycles. These improved results suggest that parenteral oestradiol valerate should be used to prepare the endometrium in recipients, and that the hormonal milieu of the endometrium plays an important role in the higher implantation rates obtainable in ovum donor and IVF surrogate cycles.

Concordant suppression of serum immunoreactive luteinizing hormone (LH), follicle-stimulating hormone, alpha subunit, bioactive LH, and testosterone in postmenopausal women by a potent gonadotropin releasing hormone antagonist (detirelix).

The purposes of the current study were 2-fold: 1) to assess the effects of a new antagonistic analog of GnRH [N-Ac-D-Nal(2)1, D-pC1-phe2, D-Trp3, D-hArg (Et2)6, D-Ala10] GnRH, or detirelix (Syntex Research) on gonadotrope function as reflected by serum levels of immuno- and bioassayable LH, and immunoactive FSH and alpha-subunit concentrations in postmenopausal, hypergonadotropic women; and 2) to determine if androgen production in the postmenopausal ovary is gonadotropin dependent. Six normal postmenopausal women were studied. Each volunteer received doses of 1, 5, and 20 mg detirelix sc in a random order separated by at least a 1-week interval. Serum LH, FSH, and alpha-subunit were measured by RIA at frequent intervals for 72 h after each injection. Bioactive LH levels were measured at 0, 24, 48, and 72 h after injection by a mouse Leydig cell bioassay, to permit comparison of biological with immunological LH activity. The steroids testosterone (T) and dehydroepiandrosterone sulfate were measured before injection and 12 (T only), 24 and 48 h after injection of the 20 mg dose. Immunoactive levels of serum LH and FSH were both suppressed in a dose-dependent manner, but LH suppression was greater than that of FSH. Maximum LH suppression (mean +/- SEM) after the 1, 5, and 20 mg doses was 40.2 +/- 7.0%, 63.2 +/- 3.4%, and 75.8 +/- 2.2%, respectively. For the same doses, maximum FSH suppression was 18.0 +/- 6.0%, 25.6 +/- 4.6%, and 39.6 +/- 2.7%. LH levels remained suppressed below baseline for up to 72 h after the 20 mg dose. Bioactive LH changes closely paralleled those of immunoactive LH. Mean LH suppression (area under the serum concentration curve) during the first 24 h after injection was 23.5 +/- 6.2% for the 1-mg dose, 47.2 +/- 4.7% for the 5-mg dose, and 61.0 +/- 2.1% for the 20-mg dose. Mean percent FSH suppression during the first 24 h, calculated in the same manner, was 6.8 +/- 3.9% (1 mg), 14.5 +/- 2.9% (5 mg), and 18.2 +/- 2.6% (20 mg). Serum alpha-subunit concentrations were significantly suppressed by 1 h after dosing with the 5- and 20-mg doses (P less than 0.05), and remained suppressed throughout the 72-h sampling period. Gonadotropin dependence of steroidogenesis in the postmenopausal ovary was suggested by a significant suppression of serum T concentrations after the 20-mg dose of detirelix.(ABSTRACT TRUNCATED AT 400 WORDS)

Treatment of uterine leiomyomas and hirsutism with nafarelin.

Nafarelin treatment reduces both uterine and myoma volume, induces amenorrhea and improves blood indices in women with uterine leiomyomas. The gonadotropin releasing hormone analog is also effective in decreasing hair growth in women with hirsutism that is associated with excess ovarian androgen production.

Use of a gonadotropin-releasing hormone agonist analogue for treatment of cyclic auditory dysfunction.

A patient with cyclic luteal phase high-frequency hearing loss is described. This was documented by pre- and post-menstrual audiograms indicating a 40-dB hearing loss in the luteal phase. This had been long-standing and was resistant to oral contraceptive therapy. A gonadotropin-releasing hormone agonist (nafarelin) was used to inhibit ovarian function and was successful in preventing loss of hearing for the 6-month treatment period.

Use of an agonistic analog of gonadotropin-releasing hormone (nafarelin) to treat leiomyomas: assessment by magnetic resonance imaging.

The purposes of this study were to investigate the effect of a superactive agonistic analog of gonadotropin-releasing hormone, nafarelin, on uterine leiomyomas and to assess the use of magnetic resonance imaging in monitoring uterine and myoma size. Eleven women with uterine leiomyomas were treated with 800 micrograms of nafarelin per day for 6 months. Serum gonadotropin and estradiol concentrations were suppressed during treatment. The mean +/- SEM serum luteinizing hormone level decreased from 11.1 +/- 1.4 to 5.6 +/- 0.42 mlU/ml and follicle-stimulating hormone from 9.5 +/- 0.66 to 7.5 +/- 0.72 mlU/ml by 3 months of treatment (p less than 0.01). The estradiol level decreased from a pretreatment follicular phase mean +/- SEM of 43 +/- 8.3 to 19.8 +/- 3.1 (p less than 0.05) and 14.8 +/- 2.2 pg/ml (p less than 0.01) at 3 and 6 months of treatment, respectively. Mean pretreatment androgen levels (testosterone, androstenedione, and dehydroepiandrosterone sulfate) were low in these women and did not change significantly during treatment. Ten women had magnetic resonance imaging, which provided excellent resolution of individual uterine myomas. As assessed by magnetic resonance imaging, the largest myoma decreased in size in nine of 10 women; the mean decrease was 46% +/- 9%. Uterine volume decreased in all 10 patients; the mean decrease was 57% +/- 7%. In several women myomas reenlarged after discontinuance of nafarelin treatment. Posttreatment myomectomy was carried out in four women; there was minimal blood loss and no surgical complications. These data indicate that suppression of ovarian estrogen production with nafarelin is associated with a decrease in uterine myoma size in many women but that myomas may regrow with reinstitution of ovarian function. Magnetic resonance imaging is an excellent method by which to monitor treatment as changes in the size of the uterus, as well as individual myomas, can be assessed. The optimal use of gonadotropin-releasing hormone analogs may be in perimenopausal women or as presurgical treatment to decrease uterine and myoma size to facilitate myomectomy.

Therapeutic uses of gonadotropin-releasing hormone analogs.

Since the discovery and synthesis of gonadotropin-releasing hormone (GnRH) in 1971, numerous long-acting agonistic and antagonistic analogs have been synthesized. Agonistic analogs were found to desensitize pituitary GnRH receptors with chronic use, resulting in decreased gonadotropin secretion and a hypogonadal state. These analogs are being investigated as potential contraceptives and in the treatment of several conditions in which decreased gonadal steroid production is desired. Substantial progress has been made in these areas. The purpose of this review is to provide the clinician with data regarding the potential clinical utility of this class of peptides.

PIP: This discussion of the therapeutic uses of gonadotropin-releasing hormone analogs begins with a review of development and biochemistry. It reviews the literature, covering true gonadotropin-stimulated precocious puberty, female and male contraception, endometriosis, uterine leiomyomata, hirsutism, premenstrual syndrome and other menstrual cycle related disorders, metastatic prostate cancer, induction of ovulation, and GnRH antagonists. 2 research teams announced the structure and chemical synthesis of gonadotropin-releasing hormone (GnRH) in 1971. Since that time, numerous long-acting agonistic and antagonistic analogics have been synthesized. The majority of analogs in clinical development have resulted from d-amino acid substitutions at position 6. More hydrophobic substitutions generally have led to increased potency. Efforts are in progress to provide the most effective and practical route of administration for GnRH analogs. After initial studies using an intravenous bolus or infusion, most clinical trials have been performed with intermittent subcutaneous injections of the drug. If GnRH is given continuously, it will desensitize pituitary GnRH receptors and inhibit secretion of luteinizing hormone (LH) and follicle stimulating hormone (FSH). Many potent and long-acting agonistic analogs have been synthesized which are capable of inhibiting pituitary gonadotropin secretion. These analogs are being evaluated for conditions in which gonadal suppression is the goal. When used on a continuous basis, several of the agonistic analogs can inhibit ovulation and gonadal steroid production in the female. This means that conditions such as isosexual precocity, endometriosis, uterine leiomyomata, and hirsutism may be treated successfully. The side effects are few, toxicity appears to be low, and menstrual function returns soon after the analog is discontinued. Evidence exists of decrease in bone density after 6 months' use of 1 analog, presumably secondary to decreased serum estrogen concentrations, yet preliminary results suggest that this is reversed within 6 months of stopping treatment. The GnRH analogs have proven successful in the treatment of gonadotropin-dependent precocious puberty and in the medical treatment of metastatic prostatic carcinoma. The GnRH agonists have been less successful as a possible male contraceptive; azoospermia cannot be induced reliably when exogenous testosterone is administered to prevent impotence. GnRH antagonists may find an application for this latter indication. GnRH agonists may be used as adjunctive treatment in ovulation induction. The agonists may be useful in conditions in which it may be desirable to suppress endogenous gonadotropin secretion before administering exogenous gonadotropins.

Dose-dependent inhibition of pituitary-ovarian function during administration of a gonadotropin-releasing hormone agonistic analog (nafarelin).

To determine if treatment with the GnRH agonistic analog nafarelin could reliably block ovulation while only partially disrupting ovarian estrogen production, three degrees of pituitary-ovarian inhibition were investigated. Thirty-two women with ovulatory menstrual cycles were given 125 micrograms (group (Gp) I), 250 micrograms (Gp II), or 1000 micrograms (Gp III) nafarelin daily by intranasal spray. Twenty-seven women completed 6 months of treatment. Basal serum FSH concentrations decreased (P less than 0.01) in all groups. Suppression of serum LH was dose dependent and significant (P less than 0.01) only in Gps II and III. Pituitary desensitization to nafarelin developed in all groups. Peak LH responses to nafarelin decreased by about 70% (Gps I and II) and 95% (Gp III). Basal serum estradiol levels after 1 month of treatment were approximately 70 pg/ml (Gp I) and 25 pg/ml (Gps II and III). Serum estradiol levels increased acutely in Gps I and II, but not in Gp III, in response to each dose of nafarelin. Thus, average daily estradiol levels in Gp II were higher than those in Gp III. Serum testosterone and androstenedione levels decreased slightly (P less than 0.05; Gp II) or by 50% (P less than 0.01; Gp III) during treatment. The effects of nafarelin on ovulatory function also were dose-dependent. In Gp I there were four ovulations (progesterone, greater than 4 ng/ml) and seven instances of luteinization (progesterone, 2-4 ng/ml) during 73 months of nafarelin administration. In contrast, there were no ovulations during 58 and 44 months in Gps II and III, respectively. After discontinuance of nafarelin, ovulatory menstrual function returned rapidly in all women. In summary, inhibition of pituitary-ovarian function by daily intranasal nafarelin administration is dose dependent. Gonadotroph sensitivity to 125 micrograms is variable, and there is inconsistent inhibition of ovulation. Daily doses of 250 or 1000 micrograms analog reliably inhibit ovulation, but are associated with either moderate (Gp II) or marked (Gp III) reduction of ovarian estradiol secretion. The effects of these reduced levels of circulating estradiol on bone are not known. Further investigation, with dosage adjusted according to individual patient sensitivity, may lead to the development of a clinically acceptable contraceptive which consistently inhibits ovulation while maintaining serum estradiol levels sufficient to prevent osteoporosis.

Treatment of hirsutism with a gonadotropin-releasing hormone agonist (nafarelin).

GnRH analogs inhibit the secretion of gonadotropins and, therefore, that of estrogens and androgens of ovarian origin. The purpose of this study was to investigate the use of one superactive agonistic GnRH analog, nafarelin, in the treatment of hirsutism. Six hirsute women were treated with nafarelin (1 000 micrograms/day) for 6 months. An acute rise in serum gonadotropin levels occurred in response to nafarelin administration initially, but it lasted less than 2 weeks. Serum gonadotropin, testosterone, free testosterone, and androstenedione concentrations decreased significantly during treatment. Mean serum LH levels decreased from 17.9 +/- 4.6 (+/- SE) to 5.0 +/- 0.5 mIU/ml (P less than 0.01), and FSH decreased from 9.3 +/- 0.7 to 7.2 +/- 0.9 mIU/ml (P less than 0.05) after 1 month of treatment. The total testosterone concentration fell from 0.77 +/- 0.10 to 0.40 +/- 0.14 ng/ml (P less than 0.01) after 1 month of therapy, and free testosterone decreased from 10.7 +/- 2.7 to 4.1 +/- 1.6 pg/ml (P less than 0.01) after 3 months. Androstenedione levels decreased from 2.4 +/- 0.4 to 1.2 +/- 0.2 ng/ml (P less than 0.01) after 1 month of treatment. The mean concentrations of all of the above hormones remained suppressed throughout treatment. Serum 5 alpha-androstane-3 alpha,17 beta-diol glucuronide levels did not decrease significantly during treatment, nor did dehydroepiandrosterone sulfate levels. The mean estradiol concentration during treatment was 34.8 +/- 3.1 pg/ml. The clinical response was very good; hair growth was slower, and new hair was less coarse compared to the pretreatment period. Hirsutism scores (determined by Ferriman-Gallwey assessment of extent and quality of body hair) improved in four of the six patients. In the six patients, the mean score decreased significantly from 19.3 +/- 3.3 to 13.2 +/- 2.8 (P less than 0.05) at the end of treatment. These data demonstrate that by suppressing ovarian androgen production, nafarelin may be useful for the treatment of hirsutism associated with either increased ovarian androgen production or increased sensitivity of the hair follicle to normal concentrations of circulating androgens.

Role of serum androgens and sex hormone binding globulin capacity in the evaluation of hirsutism in women.

Serum samples from 23 hirsute women and 23 non-hirsute women matched for age and deviation from ideal weight were analyzed for total testosterone (T), percent free testosterone (% FT) and sex hormone binding globulin capacity (SHBG). The % FT was assayed by 2 methods, using diluted serum in equilibrium dialysis (EQD) and using undiluted serum in centrifugal ultra-filtration (UF). SHBG was measured by a DEAE cellulose filter assay and T by radioimmunoassay. The two methods for determining % FT correlated well. There was considerable overlap between the hirsute and control groups for all of the measured parameters. The discrimination between the 2 groups provided by the indirect estimate of free testosterone obtained from the ratio of T to SHBG was at least as good as that provided by the free testosterone derived from ultrafiltration or dialysis.

Isolated angiitis of brain in pregnancy and puerperium.

Isolated angiitis of the brain in labor and puerperium is described. Persistent headaches in a preeclamptic patient in the postpartum period usually suggests either persistent preeclampsia or subarachnoid hemorrhage. Isolated vasculitis of the brain, which was diagnosed in the present case, should be considered as it responds to medical (pharmacologic) treatment.

Results of conservative management of premature rupture of the membranes.

The maternal and fetal outcome of a conservative management protocol, at a tertiary care center, for premature rupture of membranes between 25 and 34 weeks' gestation was reviewed for the 2-year period 1980 to 1981. There were 139 patients with premature rupture of the membranes prior to 37 weeks' gestation, 47 with premature rupture of the membranes less than 24 hours prior to delivery, and 92 in whom premature rupture of the membranes occurred 24 hours or more before delivery. There was a significant difference in the incidence of chorioamnionitis and endometritis between patients in whom premature rupture of the membranes occurred 24 hours or more before delivery and patients in whom delivery took place within 24 hours (p less than 0.001). However, neither prolongation of pregnancy with premature rupture of the membranes beyond 24 hours nor use of betamethasone was associated with any increase in maternal or neonatal infectious morbidity. Neonatal mortality was 3.3% and was related only to lower gestational age.