Paul F. Brenner

Comparison of pharmacodynamic properties of various estrogen formulations.

A group of 23 healthy postmenopausal women received one or more 2-week courses of daily administration of the following estrogen preparations: piperazine estrone sulfate (Ogen), 0.3, 0.625, 1.25, 2.5, and 5.0 mg; micronized estradiol (Estrace), 1, 2, and 10 mg; conjugated estrogens (Premarin), 0.3, 0.625, 1.25, and 2.5 mg; ethinyl estradiol (Estinyl), 10 and 20 micrograms; and diethylstilbestrol, 0.1 and 0.5 mg. Each dosage of each formulation was ingested by three women. In those women who received more than one dosage, each course was separated by a drug-free interval of at least 4 weeks. Pretreatment and posttreatment levels of follicle-stimulating hormone (FSH), luteinizing hormone (LH), corticosteroid-binding globulin-binding capacity, sex hormone-binding globulin-binding capacity, angiotensinogen, estrone, and estradiol were determined. The relative potency of these five estrogen formulations was determined by parallel line analysis for each of these responses, except LH. On a weight basis, piperazine estrone sulfate and micronized estradiol were equipotent for all responses. Conjugated estrogens suppressed FSH in a fashion equipotent to that of the other nonsynthetic estrogens; however, for all three hepatic parameters, the response was exaggerated twofold to threefold. The synthetic estrogens, diethylstilbestrol and ethinyl estradiol, were relatively more potent on a weight basis for every response and produced the most marked response (fourfold to eighteenfold in excess of their FSH suppression) for the hepatic parameters.

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 effect of contraceptive steroids on hypothalamic-pituitary function.

A study was performed to obtain additional information about the effects of oral contraceptives on pituitary function. A sequential pituitary stimulation test (SST) was used to study normal control women who then received either a combination pill with 50 mug of ethinyl estradiol or an injectable or oral progestin for three weeks, after which the test was repeated. The same test was also performed on five long-term oral contraceptive users. The SST consists of measurement of growth hormone (GH), thyroid-stimulating hormone (TSH), prolactin (PRL), luteinizing hormone (LH), and follicle-stimulating hormone (FSH) at frequent intervals after stimulation by hypoglycemia, thyrotropin-releasing hormone, and gonadotropin-releasing hormone. GH and TSH release following stimulation were unaffected by the use of contraceptive steroids, while PRL release was increased by both the combination pill and the progestin alone. LH and FSH release was decreased in the three short-term and most of the long-term users of the combination pills but was not decreased in two of the long-term users as well as in those receiving the progestin alone. These results indicate that the combination oral contraceptives have a direct effect upon the pituitary gland, causing an increase in prolactin release and a decrease in gonadotropin release. This effect varies among individuals receiving the same formulation and may be related to the development of syndrome of postpill amenorrhea-galactorrhea.

Radioimmunoassay of serum d-Norgestrel in women following oral and intravaginal administration

Serum level of dl-norgestrel (dl-Ng) were measured by a special radioimmunoassay method after oral and intravaginal administration. 3 women received .075 mg/day dl-Ng orally for 5 days, and 3 others received 50 or 100 mg dl-Ng via a polysiloxane elastomer placed in the vagina for 3 weeks. The radioimmunoassay method proved to be highly effective; cross reacting with less than .01% 1-Ng. Circulating levels of dl-Ng were detectable 30 minutes after oral ingestion, and reached peak values of 2, 1.7 and 1.5 ng/ml in 1 and 2-3 hours, respectively. Serum levels fell rapidly thereafter, reaching levels of .2-.4 ng/ml within 24 hours after injection. Serum dl-Ng levels rose rapidly after insertion of the intravaginal device, and reached peak values of 5 ng/ml and 7-11 ng/ml with 50 and 100 mg dl-Ng, respectively, within 24-48 hours after insertion. Serum dl-Ng levels then declined to about 30-40% of initial treatment concentrations. During subsequent cycles, serum dl-Ng levels remained relatively constant at 1-3 ng/ml. Concentrations declined rapidly to .2 ng/ml within 5-7 days after removal of the device. Preovulatory patterns of estradiol were observed, but ovulation did not occur, as evidenced by low progesterone values. During the 1st and 2nd treatment cycles, withdrawal bleeding began at times ranging from the day of removal to 5 days after removal. In the later treatment cycles, withdrawal bleeding began prior to removal of the device. The results indicate that the more constant release of dl-Ng with the intravaginal ring provides better control of irregular bleeding than orally administered dl-Ng.

Pregnancies associated with sperm concentrations below 10 million/ml in clinical studies of a potential male contraceptive method, monthly depot medroxyprogesterone acetate and testosterone esters

A potential male contraceptive approach was evaluated in clinical trials involving monthly injections of depot medroxyprogesterone acetate and either subdermal implants of testosterone propionate or monthly injections of testosterone enanthate. Pregnancies occurred in partners of 9 men with recent sperm counts of 10 million/ml or below. In 5 of the 9 instances, the sperm counts were less than 1 million/ml. It appears that male contraceptive methods involving spermatogenic suppression may require attainment and maintenance of azoospermia. The pregnancy rate cannot be calculated, because the extent of other contraceptive use is uncertain. There were no spontaneous abortions. 6 pregnancies were carried to term, and all progeny were normal, based on physical examination at birth or 3 months after birth.

Differential diagnosis of abnormal uterine bleeding

The causes of abnormal uterine bleeding include a wide spectrum of diseases of the reproductive system and nongynecologic causes as well. The differential diagnosis of abnormal excessive uterine bleeding includes organic causes that may be subdivided into reproductive tract disease, iatrogenic causes, and systemic disease. Reproductive tract disease that may result in abnormal uterine bleeding comprises the complications of pregnancy (threatened, incomplete, or missed abortion, ectopic pregnancy, trophoblastic disease, placental polyp, and subinvolution of the placental site), malignant tumors (endometrial, cervical, vaginal, vulvar, and oviduct malignancies and granulosa theca cell ovarian tumors), infection (endometritis, salpingitis), and other benign pelvic disorders (traumatic lesions of the vagina, severe vaginal infections, foreign bodies, cervical polyps, cervical erosion, cervicitis, submucous uterine leiomyomas, adenomyosis, endometriosis, and endometrial polyps). Iatrogenic causes of abnormal uterine bleeding include sex steroids, hypothalamic depressants, digitalis, phenytoin, anticoagulants, and intrauterine contraceptive devices. Systemic diseases that may cause abnormal uterine bleeding include hypothyroidism, cirrhosis, and coagulation disorders. Abnormal uterine bleeding that occurs in a woman of reproductive age should be considered the result of complication of pregnancy until proved otherwise. Abnormal uterine bleeding occurring in a woman of perimenopausal or postmenopausal age should be considered the result of a malignancy until proved otherwise. Menorrhagia occurring in an adolescent should be attributed to a coagulopathy until proved otherwise. When an organic cause of abnormal uterine bleeding cannot be found, then by exclusion the diagnosis of dysfunctional uterine bleeding is assumed. Coagulation disorders, particularly von Willebrand disease, are more common than many physicians realize. Women with a history of high-risk factors, all adolescents with menorrhagia, women with anovulatory dysfunctional uterine bleeding who fail medical or surgical therapy, and women with ovulatory dysfunctional uterine bleeding without an anatomic uterine lesion should be screened for a coagulopathy.

Management of abnormal uterine bleeding

Patients treated for dysfunctional uterine bleeding are separated into two groups: those with acute bleeding episodes and those with chronic repetitive bleeding problems. An acute bleeding episode is best controlled with the use of high-dose estrogen. A curettage is indicated for patients with acute bleeding resulting in hypovolemia, and a curettage or hysteroscopically directed biopsies is indicated for women with risk factors for endometrial cancer who have persistent bleeding problems. The management of anovulatory dysfunctional uterine bleeding is determined by the needs of the patient. In the adolescent medroxyprogesterone acetate is administered orally once a day for 10 days each month for > or = 3 months, and the patient is monitored closely thereafter. Oral contraceptives are used for women of reproductive age with anovulatory bleeding episodes who also require contraception. Clomiphene citrate is used for women of reproductive age with anovulatory bleeding who want to conceive. Oral medroxyprogesterone acetate is administered 10 days each month for 6 months for the treatment of anovulatory dysfunctional uterine bleeding alone in this age group. For the perimenopausal patient dysfunctional uterine bleeding may be treated by the administration of cyclic progestin or cyclic conjugated equine estrogens for 25 days with the concomitant administration of medroxyprogesterone acetate for days 18 to 25. The perimenopausal patient with dysfunctional uterine bleeding who is a nonsmoker and does not have evidence of vascular disease may also be treated with low-dose combination oral contraceptives. The long-term treatment for women with ovulatory dysfunctional uterine bleeding is the most difficult type of dysfunctional uterine bleeding to manage. The long-term therapy is directed at the reduction in menstrual blood loss. For these patients prolonged progestin use, oral contraceptives, nonsteroidal antiinflammatory drugs, antifibrinolytic agents, danazol, and as a last resort gonadotropin-releasing hormone agonists are part of the therapeutic armamentarium. A combination of two or more of these agents is often required to successfully control the abnormal bleeding. For patients who no longer desire future fertility and have associated pelvic pathologic disorders or for those who fail all medical regimens, surgical therapy may be considered. Either hysterectomy or endometrial ablation has been used. Patients with von Willebrands disease and excessive menstrual blood loss may be misdiagnosed as having dysfunctional uterine bleeding. van Willebrands disease is the most common bleeding disorder and is present in approximately 1% of the population. It is much more common than previously recognized. There are improved diagnostic tests to identify this disorder and, most important, there is a high-concentration desmopressin acetate nasal spray available as treatment that does not involve the risk of transmission of hepatitis and human immunodeficiency virus.

Radioimmunoassay of serum medroxyprogesterone acetate (Provera) in women following oral and intravaginal administration.

A radioimmunoassay (RIA) method for measuring medroxyprogesterone acetate (MPA, Provera) in serum has been developed utilizing benzene:iso-octane extraction, 3H-MPA to assess procedural losses, goat anti-MPA-3-(0-carboxymethyl) oxime-bovine serum albumin serum and dextran-coated charcoal separation. Control serum blanks were undetectable, 200 pg/ml of MPA was measurable with a high reliability, and intra- and interassay coefficients of variation were 6 and 13 percent, respectively. MPA added to control serum was quantitatively recovered. Serum MPA levels measured in 2 women after ingestion of 10 mg MPA rose to 3.4 to 4.4 ng/ml within 1 to 4 hours after oral intake and fell rapidly thereafter to 0.3 to 0.6 ng/ml within 24 hours. Insertion of Silastic intra-vaginal rings (IVRs), containing 100 or 200 mg of MPA, into 4 women for periods of 3 weeks resulted in a rapid rise of serum MPA after insertion, rather stable MPA levels of 0.9 to 1.6 ng/ml while the IVRs were in place, and a rapid decline of serum MPA following IVR removal. Serum estradiol-17beta and progesterone concentrations, measured about 3 times a week in these patients, indicated that ovulation was consistently inhibited. The serum MPA levels observed in this study were approximately 5 times lower than those reported by other investigators using a double-antibody RIA of MPA in unextracted serum.

A radioimmunoassay for norethindrone (NET): Measurement of serum net concentrations following ingestion of net-containing oral contraceptive steroids

A sensitive and reliable radioimmunoassay (RIA) for the measurement of norethindrone (NET) in serum has been established employing anti-11 alpha-hydroxynorethindrone 11-hemisuccinyl-bovine serum albumin serum in conjunction with norethindrone-3-(0-carboxymethyl) oximino-[125I]-iodohistamine. Of a number of ring A reduced NET metabolites, only 17 beta-hydroxy-17 alpha-ethinyl-5 beta-estran-3-one (43%) and 17 alpha-ethinyl-5 alpha-estrane-3 beta, 17 beta-diol (15.7%) cross-reacted appreciably in this RIA. Ethinyl estradiol (EE2) and mestranol (MEE2) exhibited cross-reactions of only 1.1 and 0.4%, respectively. Serum NET levels were measured in four groups of 3 women, each ingesting either 1 mg NET plus 0.05 mg MEE2 (Norinyl 1 + 50 or Ortho Novum 1/50), 0.5 mg NET plus 0.035 mg EE2 (Brevicon) or only 0.35 mg NET (Micronor) daily for 5 consecutive days. Peak serum NET levels were observed within 1/2 to 4 hours after oral intake and fell precipitously thereafter. After reaching a maximum, serum NET concentrations declined in a manner consistent with at least two disposition phases. The average half-life for the first disposition phase was 2.3, 3.4, 3.9 and 4.4 hours in subjects ingesting Norinyl 1 + 50, Ortho Novum 1/50, Brevicon and Micronor, respectively. Peak and 3-hour post-ingestion serum NET concentrations were dose-related but showed considerable subject-to-subject variations. Following discontinuation of tablet intake, serum NET levels remained detectable (greater than 0.05 ng/ml) for at least 5 days in all 3 women who had taken Ortho Novum 1/50, but in none of the other 9 volunteers. These results suggest that different preparations of identical doses and combinations of oral contraceptive steroids may yield different serum NET profiles. However, due to considerable subject-to-subject variations, larger numbers of subjects are required for a conclusive investigation.

Study of medroxyprogesterone acetate and testosterone enanthate as a male contraceptive

The effect of im injections of medroxyprogesterone acetate (100 or 150 mg) and testosterone enanthate (200 mg) over a 4-month period on spermatogenesis and serum testosterone levels was studied in 14 healthy, normal men. Treatment reduced sperm counts and suppressed gonadotropin levels in all subjects. 10 subjects showed sperm counts of less than 5 million/ml, though only 2 became azoospermic. A return to pretreatment sperm concentrations was not observed until 16-41 weeks after the last injection. Testosterone enanthate did not maintain serum testosterone levels at pretreatment values, though none of the subjects reported a decrease in libido. 1 subject developed unilateral gynecostamia during treatment. It is concluded that the doses used in this study are probably insufficient to provide effective contraception in males.