Daniel R. Mishell

A decade’s experience with an individualized clomiphene treatment regimen including its effect on the postcoital test

During a 10-year period, 428 women received clomiphene citrate according to a graduated therapeutic regimen in which the dose of clomiphene and the laboratory studies were individualized according to each patients history, examination and response. Of the 428 patients, 85.3% ovulated and 42.8% conceived. The great majority of those who conceived did so during the first three ovulatory cycles. There was no evidence that clomiphene therapy was associated with the induction of another cause of infertility. Overall, 88.2% of those with no other causes for infertility who ovulated also conceived. However, only 7.8% of those who had one or more factors in addition to anovulation became pregnant. There was no evidence that clomiphene adversely affected the postcoital test, as only 15% of the patients had poor cervical mucus. The low rate of complications of this treatment, 5.1% cyst formation as well as the 14% abortion rate and the 2.6% congenital anomaly rate and the excellent gestational outcome in those who conceived support the use of this treatment regimen.

Serum testosterone concentrations in women throughout the menstrual cycle and following HCG administration.

Abstract Serum testosterone (T) concentrations, measured by a specific, precise, and sensitive radioimmunoassay in 40 women with apparently normal menstrual cycles averaged 34.6 ± 10.3 (S.D.) ng. per cent and ranged from 14 to 59 ng. per cent. Mean serum T concentrations, assayed daily in eight women throughout an entire ovulatory cycle, were highest around the midcycle LH peak and higher during the follicular than during the luteal phase of the cycles. Averages of daily serum T concentrations, when determined for each individual woman for the entire cycle, varied significantly among the eight subjects studied, ranging from 23.1 to 39.0 ng. per cent. Coefficients of variation of serum T levels in these eight individual cycles averaged 22 per cent. HCG administration to three of these eight women during the luteal phase of their subsequent cycle resulted in a significant rise of serum T concentrations in only one subject. These data indicate that mean serum T concentrations in normal women are subject to small but significant changes during the course of the menstrual cycle. Despite these cyclic changes, as well as day-to-day variations, serum T concentrations in normal women largely fall into a relatively narrow range. Repeated serum T concentrations which consistently exceed 55 ng. per cent (2 S.D. above the mean) may be regarded as documentation of androgen excess.

Clinical performance and endocrine profiles with contraceptive vaginal rings containing a combination of estradiol andd-norgestrel

Contraceptive vaginal rings, impregnated with d-norgestrel (77 mg) and estradiol (29-66 mg) were studied in 10 subjects aged 24-28. 5 subjects were studied for 3 cycles and 5 for 6 cycles. The rings were inserted (on Day 5) for 3 weeks and removed for 1 week to allow withdrawal bleeding. Serum samples were obtained at least 3 times/week; estradiol and d-norgestrel were assayed in each sample, and progesterone weekly. Clinical acceptance was good. Ovulation was inhibited in all treatment cycles and resumed within 1 month following completion of the trial. There was regular withdrawal bleeding, no episodes of failure of withdrawal bleeding, and only 3 days of breakthrough spotting. Serum d-norgestrel levels were relatively constant in each subject except for the 1st half of the 1st treatment cycle which had slightly higher levels. Serum estradiol levels rose rapidly following insertion of the ring to levels between 100-300 pg/ml, but then declined over the next few days to levels generally less than 50 pg/ml. After treatment, mean levels of the binding capacity of corticosteroid-binding-globulin did not become significantly elevated and serum triglycerides declined. This method has the advantage of inhibition of ovulation and good control of bleeding without the disadvantage of producing some adverse metabolic effects.

The relation of serum 17-hydroxyprogesterone and estradiol-17β levels during the human menstrual cycle ☆

Abstract Concentrations of 17-hydroxyprogesterone (17-OHP) were measured in serum samples obtained daily through 9 menstrual cycles. These samples had previously been assayed for estradiol, progesterone, luteinizing hormone (LH), and follicle-stimulating hormone. The concentration of 17-OHP increased at mid-cycle and continued to be high throughout the luteal phase of the cycle. The first sustained rise in 17-OHP levels was associated with the initiation of the mid-cycle LH surge. The results of this study indicate that the mid-cycle rise of 17-OHP may well be one of the earliest indicators of luteinization of the follicle as this hormone appears to be initially secreted by luteintzed thecal cells and then by the corpus luteum. It is concluded that estradiol levels rather than 17-OHP levels provide a good index of follicular maturation, whereas rising concentrations of the latter hormone indicate luteinization of the follicle.

Effects of the antiprogesterone RU 486 in normal women: II. Administration in the late follicular phase

RU 486, a synthetic steroid with antiprogesterone receptor activity, was used to investigate the importance of progesterone on gonadotropin secretory dynamics in the midcycle of the normal menstrual cycle. Six normally cycling women were followed for three consecutive cycles. During each cycle, blood samples were obtained beginning on day 10 and continued until menses. After a control cycle, 100 mg RU 486 was given orally between days 10 and 17. The patients were followed for a posttreatment cycle with no medication. When RU 486 was given before the midcycle, the luteinizing hormone surge was delayed by 15.0 +/- 2.1 days after ingestion of the last pill, resulting in cycles of 40.6 +/- 2.6 compared with 28.0 +/- 2.3 days (p less than 0.01). During RU 486 administration and at the time a normal luteinizing hormone surge was anticipated, an attenuated luteinizing hormone/follicle-stimulating hormone surge was noted that was not followed by a rise in progesterone. After the attenuated surge a normal luteinizing hormone/follicle-stimulating hormone level occurred, with a normal rise in progesterone. Estradiol levels during RU 486 administration decreased during treatment, indicating a possible direct action of RU 486 on the ovary.

Conservative management of adnexal torsion

OBJECTIVES Our purpose was to evaluate morbidity in patients who underwent conservative therapy, ovarian cystectomy, for adnexal torsion compared with those who underwent salpingo-oophorectomy and to determine predictive factors associated with the ability to perform conservative surgery. STUDY DESIGN A retrospective review of all women < 40 years old with adnexal torsion treated between May 1, 1989, and Dec. 31, 1991, was performed. All potentially viable adnexa were untwisted, and cystectomies were performed unless the adnexa failed to reperfuse. RESULTS Ninety-four women were studied, and of these 61 (65%) received ovarian cystectomies and 33 (35%) underwent salpingo-oophorectomy. No thromboembolic complications or increase in postoperative morbidity was seen. Patients requiring salpingo-oophorectomy had more preoperative fevers and leukocytosis, larger masses, and higher degrees of torsion. CONCLUSION Conservative surgery with untwisting of the adnexa followed by cystectomy can be performed in reproductive-age women with adnexal torsion who have potentially viable adnexa.

An extended regimen of clomiphene citrate in women unresponsive to standard therapy

An extended regimen of clomiphene consisting of 250 mg of clomiphene for 8 days followed by the administration of 10,000 IU of human chorionic gonadotropin (hCG) 6 days later was administered to 13 oligomenorrheic women who had previously failed to ovulate when treated with 250 mg of clomiphene for 5 days and hCG. Eight of these 13 women ovulated. Their postovulatory mean progesterone (P) level 7 days after hCG was 16 +/- 2 ng/ml. Three pregnancies occurred during 25 treatment cycles. Posttreatment estrogen levels were higher when women were treated for 8 days than for 5 days. Women ovulating after 8 days of treatment had increased concentrations of luteinizing hormone (LH) and testosterone (T) prior to hCG administration and higher pretreatment levels of estrogen and T, compared with women who did not ovulate. Changes in the timing of hCG administration may induce ovulation in some women who fail to ovulate when hCG is given on day 14. Because this 8-day regimen of clomiphene and hCG was successful in more than 50% of women failing to ovulate after 5 days, this regimen should be used prior to human menopausal gonadotropin (hMG) therapy.

A double-antibody radioimmunoassay for serum progesterone using progesterone-3-(o-carboxymethyl)oximino-[125l]-iodo-histamine as radioligand

A reliable, convenient and economical radioimmunoassay (RIA) for serum progesterone has been established and tested. This procedure employs diethyl ether extraction followed by RIA utilizing rabbit anti-11 alpha-hydroxyprogesterone 11-hemisuccinyl-bovine serum albumin (progesterone-11 alpha-BSA) serum, progresterone-3-(O-carboxymethyl) oximino-[125I]-iodohistamine (progesterone-3-[125I]) as radioligand and goat anti-rabbit gamma globulin as second antibody. In conjunction with antiprogesterone-11 alpha-BSA serum, the overall assay specificity of the progesterone-3-[125I] RIA is similar to that of the [3H]-progesterone method using dextran-coated charcoal. The results of serum progesterone measurements during the menstrual cycle obtained by the progesterone-3-[125I] RIA appear comparable to those of [3H]-progesterone assays which employ similar anti-progesterone-11 alpha-BSA sera. The progesterone-3-[125I] double-antibody RIA, however, is more convenient and less expensive than the [3H]-progesterone RIA method.

A modified technique for the assay of progesterone in blood using celite column chromatography

Abstract A modified technique for the assay of progesterone in blood is presented. The procedure consists of three main steps: 1) ether extraction, 2) rapid and complete separation of progesterone from more polar steroids by the use of celite column chromatography, and 3) radioassay of progesterone by competitive protein binding. This assay method has a sensitivity of 0.1 ng and excellent specificity with low values for blank samples. The precision of this assay technique is comparable with other reported methods. This method offers two main advantages in comparison with previously described procedures. First, the celite column chromatography provides a rapid technique of separation of progesterone from other cross reacting steroids with a recovery of greater than 75 per cent. Secondly, the more polar steroids can be eluted subsequently and assayed separately. Thus, the assay of other steroids can be easily performed using the same serum extract.

Termination of early gestation with vaginal prostaglandin F2α tablets

The abortifacient activity of prostaglandin F2α was investigated by placing one or two 50 mg tablets of prostaglandin F2α in THAM salt into the vagina of nine women less than 4 weeks pregnant at intervals of 2 to 4 hours for a 24 hour period. Serum levels of HCG, estradiol (E2), progesterone and 17α-hydroxyprogesterone were measured by radioimmunoassay prior to starting therapy and at frequent intervals thereafter for 48 hours. All but two patients had significant side-effects, mainly diarrhea and vomiting, indicating that systemic absorption took place. Although bleeding was induced in 8 of 9 women, only 3 had complete abortions. A D&C was performed on all patients 48 hours after starting therapy. A significant fall in HCG levels was noted only in the patients who aborted. Only 3 of the 9 women had significant changes in steroid levels. A fall in progesterone and 17α-hydroxyprogesterone occurred in the 3 women who aborted and took place following the fall in HCG. Estradiol levels remained in the same range in all subjects. These findings indicate that prostaglandin F2α when administered in this vehicle and this dosage is relatively ineffective as an abortifacient. When effective, its action would appear to be due to contractions of uterine muscle and not secondarily to luteolysis.