Treatment of congenital osteopetrosis in the rabbit with high-dose 1,25-dihydroxyvitamin D.

Osteopetrosis is a congenital metabolic bone disease characterized by skeletal sclerosis resulting from defective osteoclast-mediated bone resorption. Osteopetrosis has been described in several animal species (mouse, rat, and rabbit) and in children. Bone marrow transplantation, originally shown to reverse the skeletal sclerosis in some animal mutations, has been effective in curing osteopetrosis in some children. Unfortunately, not all children with osteopetrosis are candidates for or respond to bone marrow transplantation. Recent studies have shown that several animal mutations and some children inheriting osteopetrosis have significantly elevated serum levels of 1,25-(OH)2D. Based on the possibility that there may be a resistance to 1,25-(OH)2D, high-dose calcitriol therapy has been used to treat some children and stimulated some parameters of resorption. In this study, we have examined the effects of high-dose calcitriol therapy on various serum and skeletal parameters in the osteopetrotic rabbit. Mutant rabbits and normal littermates were given continuous infusions of calcitriol via subcutaneously implanted osmotic minipumps for 2 weeks at a dose of 0.5, 2.5, or 25 micrograms/kg/per day. Untreated mutant rabbits are hypocalcemic and hypophosphatemic in the presence of elevated serum 1,25-(OH)2 levels in comparison with their normal littermates. Calcitriol infusions resulted in dose-dependent increases in circulating 1,25-(OH)2D levels in both normal and mutant rabbits. However, evaluation of other serum parameters and the skeletal response demonstrated significant differences between osteopetrotic and normal rabbits. At the highest dose, normal animals rapidly became hypercalcemic and osteoporotic, accompanied by weight loss and a failure to thrive; mutants remained hypocalcemic and osteopetrotic but did not exhibit the deleterious physical effects seen in treated normal littermates. Although the number of osteoclasts increased in both mutants and normals, osteoclast phenotype in the former remained abnormal. These data indicate that although very high levels of circulating 1,25-(OH)2D were achieved in osteopetrotic mutants, activation of osteoclast-mediated bone resorption with subsequent improvement of skeletal sclerosis was not observed.

The role of dietary sodium on renal excretion and intestinal absorption of calcium and on vitamin D metabolism.

Earlier studies have shown that an oral sodium (Na) load may induce hypercalciuria in previously normocalciuric subjects and may also increase intestinal calcium (Ca) absorption. To probe the cause of the increased intestinal Ca absorption, we simultaneously measured parathyroid function, serum 1,25-dihydroxyvitamin D [1,25-(OH)2D], and fractional intestinal 47Ca absorption before and after a salt load. Eleven normal subjects and two patients with postsurgical hypoparathyroidism were placed on a 10 meq Na, 400 mg Ca per day diet for 10 days, followed by another 10-day period in which the same diet was supplemented by 240 meq Na daily. Measurements were performed on the final 3 days of each phase. In the normal subjects, urinary Na excretion increased from 7 +/- 2 to 226 +/- 8 meq/day (mean +/- SEM), urinary Ca rose from 110 +/- 14 to 167 +/- 16 mg/day, serum parathyroid hormone (PTH) increased from 20 +/- 1 to 22 +/- 1 muleq/ml, serum 1,25-(OH)2D rose from 38 +/- 4 to 51 +/- 7 pg/ml, and fractional intestinal 47Ca absorption increased from 0.39 +/- 0.03 to 0.49 +/- 0.03 (P less than 0.05 for all changes). Serum Ca corrected for total protein did not change (9.9 +/- 0.1 to 9.8 +/- 0.1 mg/dl). The patients with hypoparathyroidism who were maintained on vitamin D therapy also showed increases in urinary Na (20 +/- 12 to 245 +/- 11 meq/day) and urinary Ca (271 +/- 48 to 305 +/- 43; P less than 0.05). However, there were no increases in serum PTH (13 +/- 1 to 11 +/- 1 muleq/ml), serum 1,25-(OH)2D (44 +/- 1 to 40 +/- 6 pg/ml), or intestinal Ca absorption (0.41 +/- 0.03 to 0.42 +/- 0.05). Corrected serum Ca decreased from 9.4 +/- 0.2 to 8.6 +/- 0.2 mg/dl. We conclude that in normal subjects, Na-induced renal hypercalciuria is accompanied by increased 1,25-(OH)2D synthesis and enhanced intestinal Ca absorption. Since this adaptive mechanism did not occur in two patients with hypoparathyroidism, mediation by PTH is suggested.

Pathogenetic role of 1 alpha,25-dihydroxyvitamin D in sarcoidosis and absorptive hypercalciuria: different response to prednisolone therapy.

Intestinal hyperabsorption of calcium (Ca) is frequently observed in sarcoidosis and is characteristic of absorptive hypercalciuria (AH). The potential pathogenetic role of 1 alpha,25-dihydroxyvitamin D [1,25(OH)2D] in these two conditions was sought by a careful assessment of the circulating concentration of this vitamin D metabolite and various measures of Ca metabolism before and after prednisolone therapy. In eight patients with sarcoidosis, prednisolone treatment (50 mg/day for 8 days) produced a significant fall in serum 1,25(OH)2D [4.8 +/) 1.9 to 3.3 +/- 1.0 (SD) ng/dl; P less than 0.025], concomitant with a significant decrease in the fracitional intestinal Ca absorption (alpha) from 0.58 +/- to 0.14 to 0.46 +/- 0.13 (+/- SD; P less than 0.005). Urinary Ca and serum parathyroid hormone did not change significantly. However, in six patients with AH, prednisolone therapy resulted in a nonsignificant rise in serum 1,25(OH)2D from 3.6 +/- 0.7 to 4.4 +/- 1.0 ng/dl and no significant fall in alpha (from 0.73 +/- 0.08 to 0.70 +/- 0.10). Urinary Ca was significantly increased in AH patients from 230 +/- 35 to 343 +/- 74 (SD) mg/day (P less than 0.005), while serum parathyroid hormone rose slightly. Serum 1,25(OH)2D and alpha were significantly correlated (r = 0.543; P less than 0.05) for patients with sarcoidosis but not in AH patients. These results suggest that the hyperabsorption of calcium in sarcoidosis is dependent on the serum concentration of 1,25(OH)2D, while in AH it may result from additional vitamin D-independent processes.

Bone particles from osteopetrotic mice not cured by bone marrow transplants are resorbed in normal littermates.

Osteosclerotic (oc/oc) and osteopetrotic (op/op) mice are not cured by bone marrow transplantation from normal littermates. The possibility that this is due to production of poorly resorbable bone was examined by comparing the fate of mutant and normal bone particles implanted subcutaneously in normal hosts. Bone, removed aseptically from calvarial and tibial sites of normal littermates and mutants, was cleaned of adherent soft tissue, ground and sieved to a particle size of 70-300 micron. Aliquots (17-20 mg) of bone from each phenotype of each stock were pelleted and implanted beneath the anterior thoracic skin of normal littermates for two weeks. Particle density in tissue sections was determined as percent of field by a point-counting method. Giant cell response was recorded as number per high-power field. Percent bone present initially was determined in pellets implanted for less than 24 hr. Bone particles were reduced in each pellet with time, about 25% of the original volume being removed in two weeks. No statistically significant differences were noted in the rates of disappearance of mutant and normal bone or in the percentage or number of giant cells in implants of mutant and normal bone in either stock. Furthermore, these values were not different from identical studies in microphthalmic mice, an osteopetrotic stock cured by bone marrow transplantation. These data suggest that the failure of osteopetrotic and osteosclerotic mice to be cured by bone marrow transplants from normal littermates is not due to the presence of unresorbable bone.

Skeletal status of men with early and late ankylosing spondylitis.

PURPOSE: To assess the influence of extent of disease on the skeletal status of men with ankylosing spondylitis (AS). PATIENTS AND METHODS: Fourteen men with AS were studied at entry and again after 15 months. Bone mineral density (BMD) was assessed by single photon absorptiometry (SPA), dual energy x-ray absorptiometry (DXA), and quantitative computed tomography (QCT). Calciotropic hormones and bone turnover were also assessed, and biopsies of iliac crest and skin were taken after tetracycline double-labeling from 10 subjects. Clinical evaluation and Health Assessment Questionnaires were used to assess functional status. RESULTS: Of the 14 participants, 7 had sacroiliitis alone without radiologic evidence of spinal involvement (early disease) and 7 had sacroiliitis with extensive vertebral calcifications and immobilization (late disease). QCT baseline lumbar spine BMD was very low in both groups compared with normative standards (Z score = -3.08 +/- 1.83, P < 0.0001) and did not change significantly over 15 months. This low BMD was more marked in late disease than in early disease subjects (P < 0.01). DXA BMD at the lumbar spine was lower than predicted in early disease subjects (Z score = -1.08 +/- 0.67, P = 0.005) but not in the late disease group. DXA BMD was also low at the all three hip sites (Z score = -0.96 +/- 0.86, P < 0.01). Significant differences between late disease group and normative values were apparent at all hip sites. Values in early disease subjects, however, did not differ from age-predicted norms. Bone mineral status did not change significantly over the 15-month period of observation. Circulating parathyroid hormone (PTH) and vitamin D metabolites were normal in both groups as were creatinine clearance and urinary excretion of calcium and hydroxyproline. Osteocalcin levels were normal in all but the two youngest subjects in the early disease group. Histomorphometry of the iliac crest showed no consistent change in bone turnover. Bone volume and trabecular width were low in many cases. Cancellous bone volume correlated with lumbar spine BMD by QCT (r = 0.69, P = 0.026) but not with DXA. Although beneficial changes occurred in exercise tolerance and pain over time, anthropometric measurements did not improve. CONCLUSION: BMD is low in both the axial and peripheral skeleton in men with AS and is independent of spinal immobilization. Anterioposterior lumbar spine DXA in late AS is less useful than QCT in determining the degree of osteopenia in late AS. Bone mineral deficits in AS do not reflect measurable metabolic derangement or hypogonadism. Although bone histomorphometry suggests both trabecular thinning and loss of structural elements as mechanisms involved in low bone volume, the exact cause of osteopenia in AS remains to be determined.

Synthesis and estrogenic properties of 17-epi-ethynylestradiol and its ether derivatives epimestranol and epiquinestrol.

The synthesis of 17-epi-ethynylestradiol (10), the 17 beta-ethynyl-17 alpha-ol epimer of the well-known orally active estrogen, ethynylestradiol (1), was achieved by LiA1H4 reduction of epoxide 9, as well as by demethylating epimestranol (11) with CH3MgI. Compound 11 was obtained by the unusual 17 beta-ethynylation of estrone 3-methyl ether 22 under equilibrating conditions. The in vitro estrogen receptor-binding affinity and the oral estrogenicity in the rat for the 17-epi compounds 10, 11 and 20 (epiquinestrol) was evaluated. Despite moderate estrogen receptor-binding affinity, compound 10 was devoid of measurable estrogenicity at 10 mg/kg or antiestrogenicity at 3 mg/kg.

17alpha-Ethyl-20alpha-and -20beta-dihydroprogesterones and other 17alpha-ethyl-substituted pregnanes as potential contragestational agents.

The 17alpha-ethyl-substituted analogs of the two epimeric 20-dihydroprogesterones, allopregnadedione and pregn-5-ene-3,20-dione, were synthesized and evaluated for their possible oral contragestational (postcoital antifertility) activity in the rat. The compounds, though bound strongly to the progesterone receptor in vitro, were inactive preimplantively at 10 mg/kg and postimplantively at 40 mg/kg in vivo.

PIP: 17alpha-20alpha- and 20beta-dihydroprogesterones and other 17alpha-ethyl-substituted pregnanes as potential contragestational agents were investigated in the rat, and the syntheses of 17 alpha-ethyl-substituted analogs of the 2 epimeric 20-dihydroprogesterones, allopregnanedione and pregn-5-ene-3,20 dione are presented. The compounds were administered orally to 5 rats on Days 1-6 of gestation for studies related to effects on implantation or on Days 9-12 of gestation for studies related to drug effects on pregnancy after implantation. Postmortem examination was carried out between Day 14 and Day 21 of gestation. The compounds were strongly bound to the pr ogesterone receptor in vitro but were inactive preimplantively at 10 mg/kg and postimplantively at 40 mg/kg in vivo.

Effects of a sustained release formulation of the gonadotrophin-releasing hormone agonist histrelin on serum concentrations of gonadotrophins and oestradiol, and ovarian LH/human chorionic gonadotrophin receptor content in the rat.

Pituitary and ovarian function were studied during the loss and recovery of oestrous cyclical activity in rats following treatment with a sustained release formulation of the gonadotrophin-releasing hormone (GnRH) agonist [imidazole benzyl-D-His6,Pro9-ethylamide]-GnRH (histrelin). A single s.c. injection of microencapsulated histrelin (10-300 micrograms peptide/kg) induced a dose-dependent disruption of normal oestrous cyclical activity with a persistent dioestrous-like vaginal cytology. In preliminary studies, pituitary gland stimulation and desensitization were demonstrated when serum LH and FSH levels were greater 1 week after administration of 10 micrograms microencapsulated histrelin/kg compared with 300 micrograms microencapsulated histrelin/kg. Changes in pituitary and ovarian function were assessed over time following injection of microencapsulated histrelin (100 micrograms peptide/kg). LH secretion was maximal within 8 h and then gradually declined, remaining at dioestrous levels from days 7 to 28. Serum oestradiol concentrations remained low and rose above dioestrous levels only on day 28. In contrast, ovarian LH/human chorionic gonadotrophin (LH/hCG) receptor content fell within 8 h and, after a nadir on day 7, slowly returned to dioestrous levels by day 28. The increase in ovarian LH/hCG receptor content preceded any significant change in pituitary gonadotrophin secretion, indicating a differential pattern of recovery for pituitary and ovarian function. Subsequent studies tested the possibility that these temporal differences in pituitary and ovarian function may result from histrelin acting directly on these tissues. Treatment with histrelin microcapsules (300 micrograms peptide/kg) prevented any increase in LH secretion in response to a GnRH challenge 3 days later, indicating a direct action of histrelin on the pituitary gland.(ABSTRACT TRUNCATED AT 250 WORDS)

Bromperidol, a new butyrophenone neuroleptic: a review.

This review compares and contrasts the preclinical pharmacology of bromperidol with another butyrophenone neuroleptic, haloperidol, and the phenothiazine neuroleptic chlorpromazine. Its pharmacokinetics, biotransformation, and safety in several laboratory animal species are also summarized. These preclinical data support its use as an antipsychotic agent and show that it is well absorbed following oral administration with an apparent elimination half-life of approximately 24 h, supporting a once-daily dose regimen. Animal toxicity (including acute- and multiple-dose toxicology and reproductive and mutagenicity studies) show that bromperidol is well tolerated.

Overuse syndromes in adult athletes.

Approximately 50% of all sports participants will be injured at some point, and at least half of these injuries will be attributed to overuse. This article provides an in-depth review of the presentation, diagnosis, and treatment of the most common overuse injuries encountered in the adult population: epicondylitis, shoulder impingement/rotator cuff tears, patello-femoral dysfunction, and Achilles tendinitis. Stress fractures, the "ultimate" overuse injuries, are also discussed.

Acute injuries and specific problems in adult athletes.

Special considerations need to be given to specific groups of adult athletes. The most common problems and needs of female and older athletes are discussed in the first section of this article. The second section reviews the diagnosis and management of certain acute injuries most frequently encountered in adult athletes. The last section discusses the differentiation between tarsal tunnel syndrome and plantar fasciitis, chronic compartmental pressure syndrome and medial tibial stress syndrome ("shin splints"), and pelvic stress fractures and osteitis pubis, some commonly encountered difficult diagnoses.

Colchicine: effects upon urinary hydroxyproline excretion in patients with scleroderma.

Three patients with scleroderma were given intravenous infusions of colchicine (2-4 mg/day) for 3 days. Twenty-four-hour urine collections were assayed for total hydroxyproline (HYPRO), an index of collagen resorption, and for nondialyzable polypeptide HYPRO, an index of collagen synthesis. During the colchicine infusions there was a fall in total urinary HYPRO and a slight increase in the per cent nondialyzalbe HYPRO in each patient. The hydroxylysyl-galactosyl-glucose (HGG) to hydroxylysyl-galactose (HG) ratios were not strikingly different in two samples, with the greastest differences in HYPRO excretion. Our results suggested that total body collagen catabolism had diminished without a concomitant decrease in synthesis. In contrast to provocative reports in the literature, these data do not support the hypothesis that administration of colchicine in doses tolerated in man can either inhibit synthesis of new collagen, increase degradation of mature collagen, or be of use in treatment of fibrotic states.

Development of an animal model for quantitatively evaluating effects of drugs on endometriosis.

The present study was conducted to induce endometriosis in an experimental animal model in which the condition and its response to pharmacologic agents could be quantified. Endometriosis was induced in New Zealand White rabbits by transplanting endometrial sections into various sites throughout the peritoneum. After 7 weeks, the mean implant weight increased in concomitant controls from 10.3 to 89.0 mg. In the next 8 weeks, endometrial implant weight increased to 163.6 mg. Daily subcutaneous administration of a luteinizing hormone-releasing hormone agonist, histrelin, or oral administration of danazol, reduced the ectopic implant weight within 8 weeks to 21.7 and 46.0 mg, respectively. In a group of animals that were bilaterally ovariectomized, implant weight decreased significantly in the same 8-week period to 22.4 mg. Furthermore, histologic analysis of the endometriomas showed that ovariectomy, histrelin, or danazol treatment reduced the number of endometrial glands and atrophied the stroma. We conclude that this animal model represents an excellent method for quantitative evaluation of potential therapeutic agents for endometriosis.

Characterizing pituitary response to a gonadotropin-releasing hormone (GnRH) antagonist in monkeys: tonic follicle-stimulating hormone/luteinizing hormone secretion versus acute GnRH challenge tests before, during, and after treatment.

Pituitary sensitivity to a gonadotropin-releasing hormone (GnRH) challenge test before, during, and after GnRH antagonist administration was compared in four ovariectomized female monkeys receiving GnRH antagonist intramuscularly (IM) at increasing doses of 0.3, 1.0, and 3.0 mg/kg/day over 9 days. Three days before and 3 days after treatment, monkeys received vehicle alone. On experiment days 4, 7, 10, 13, and 16, 100 micrograms of GnRH was administered intravenously (IV) and blood drawn at 0 and 30 minutes. Before treatment, tonic follicle-stimulating hormone (FSH) and luteinizing hormone (LH) levels were 248 +/- 105 and 178 +/- 31 ng/ml, respectively; after 0.3 mg/kg/day of GnRH antagonist, FSH and LH decreased to 30 +/- 6 and 41 +/- 4 ng/ml, respectively. After treatment with either 1 mg/kg/day or 3 mg/kg/day of GnRH antagonist, both gonadotropins were undetectable in serum. Monkeys with lower initial levels of gonadotropins were suppressed by 48 hours after GnRH antagonist, while those with higher tonic gonadotropins were suppressed 6 days later (FSH: r = 0.992; LH: r = 0.833). The data show that initial physiologic status is predictive of the rapidity of the suppression response induced by a GnRH antagonist and that, after achieving pituitary suppression, responsivity to an IV GnRH challenge test may be restored before normal tonic FSH/LH secretion is regained.

Reproductive/endocrine and anaphylactoid properties of an LHRH-antagonist, ORF 18260 [Ac-DNAL1(2), 4FDPhe2,D-Trp3,D-Arg6]-GnRH.

It has been demonstrated in a variety of experiments that ORF 18260 inhibits (ED100) spontaneous and LHRH-induced ovulation in rats (10 micrograms/kg s.c.; 10 mg/kg i.g.) and hamsters (100 micrograms/kg s.c. and 100 mg/kg i.g.). Inhibition of LHRH induced ovulation appears to be competitive in nature. In normally cycling animals, efficacy varies with time of administration. In the spontaneously ovulating rat, the most effective time is 15.00 hr of proestrus; in the hamster it is 10.00 hr. Continuous administration inhibits ovulation in rats, and ORF 18260 has contragestational activity in rats and hamsters but not in guinea pigs and mice. Prostate growth in rats is inhibited at a dose of 100 micrograms/kg (s.c.). Our studies also suggest that ORF 18260 can also induce cutaneous anaphylactoid-like reactions in rats. When compound is administered intradermally in rats, ORF 18260 causes a dose-related whealing response, noticeable from the 0.01 micrograms/rat dose level.

Smooth muscle contraction as a model to study the mediator role of endogenous lipoxygenase products of arachidonic acid.

In the lung, the contraction of smooth muscle, or bronchospasm, is generally caused by an immunologic insult resulting in mast cell degranulation and the release of histamine, slow reacting substances, and other mediators of inflammation (1). Although the immediate response is bronchospasm, continued activation of this sequence of events results in a chronic inflammatory disease. In the uterus, numerous conditions can result in smooth muscle contraction. One major pathophysiological syndrome associated with increased uterine tone and severe rhythmic contraction is primary dysmenorrhea (2). In this disease state, prostaglandins have been shown to play a major role in these contractions (3,4), and inhibitors of cyclooxygenase have proven beneficial in clinical practice (5). Both dysmenorrhea and cervical ripening have been likened to inflammatory reactions due to varying degrees of vasodilation, invasion by inflammatory cells, proliferation of fibroblasts and smooth muscle contraction (6,7). Metabolism of arachidonic acid (AA) via cyclooxygenase to prostaglandins and thromboxanes and via lipoxygenase to hydroxyeicosatetraenoic acids (HETEs) and leukotrienes is an integral part of both the acute and chronic inflammatory reaction in the lung or uterus. The material reviewed here examines the effect of endogenous leukotrienes on both the lung and uterus and suggests that other smooth muscles and pathophysiological states may be more involved with the lipoxygenase pathway of AA metabolism than previously believed.

Sensitivity differences in reproductive/endocrine organs to chronically administered LHRH agonists in female rats.

The acute and chronic effects of two LHRH agonists on reproductive endocrine target organs were examined in female rats. Animals were injected twice daily with [(ImBzl)-D-His6,Pro9-NEt]LHRH (histrelin) or [D-Trp6,Pro9-NEt]LHRH for 1, 3, 5, 7, 11 or 28 days at 1, 10, 100 or 1000 micrograms/kg/day beginning in the luteal phase. The responses observed with the two agonists were similar. An initial stimulatory phase was observed on the first day of treatment with substantial increases in serum LH and progesterone levels. A significant diminution of hormone response was seen by day 3. Only 1000 micrograms/kg abolished the pituitary LH response at later treatment periods. Estrous cyclicity, ovarian and uterine weight, and progesterone and estradiol levels were inhibited in a time and dose dependent manner. The results demonstrate target organ sensitivity differences. In contrast to the relatively high doses needed to inhibit the pituitary response and decrease ovarian weight, doses as low as 1 microgram/kg were sufficient to decrease uterine weight. If these findings extrapolate to humans, it may be that conditions in which the desired therapeutic action is suppression of uterine tissue, may be treated with lower doses of LHRH agonists than conditions requiring complete gonadal suppression.

Anaphylactoid and anti-ovulatory activities of LHRH antagonists in rats.

Studies were conducted with LHRH antagonists examining the relationship of structure to anaphylactoid-like activity and the relationship of anaphylactoid-like activity to anti-ovulatory activity in rats. Substitution of basic amino acids appeared to enhance the anaphylactoid-like activity of these peptides but other complex structural characteristics may also be involved. Anaphylactoid and anti-ovulatory activities were clearly independent and potent LHRH antagonists with minimal anaphylactoid-like activity were identified.

Evaluation of the anaphylactoid activity of a new LHRH antagonist.

ORF 23541 [N-Ac-D-Nal(2)1,D-pCl-Phe2,D-Pal(3)3,Ser4,Nic-Lys5,D-Nic-Lys 6, Leu7, I-Lys8, Pro9,D-Ala10NH2; "Nal-Lys antagonist"] was identified as a potent LHRH antagonist without significant anaphylactoid activity. It blocked ovulation in proestrus rats when administered subcutaneously with an ED50 of 5.8 micrograms/kg. Much higher doses of ORF 23541 than of other antagonists were required to induce a cutaneous anaphylactoid-like reaction. Intradermal administration of ORF 23541 caused an 8.75 x 8.75 mm wheal response with estimated doses of 10.9 and 13.7 micrograms in rats and guinea pigs, respectively. These doses were at least 10 times greater than that required of other LHRH antagonists for the same response. ORF 23541 also did not alter pulmonary function in guinea pigs or dogs when administered intravenously at doses up to 10 mg. These results indicate that ORF 23541 represents a new generation of LHRH antagonists with an improved safety margin.

Relative binding affinity of norgestimate and other progestins for human sex hormone-binding globulin.

The relative binding affinity of norgestimate for human sex hormone-binding globulin was compared with that of its metabolites and other progestins by measuring their abilities to displace [3H]testosterone from this carrier protein in vitro. Norgestimate and its 17-deacetylated and 3-keto metabolites did not significantly displace [3H]testosterone from sex hormone-binding globulin at concentrations up to 10,000 nM, whereas gestodene, levonorgestrel, and 3-keto desogestrel displaced [3H]testosterone from sex hormone-binding globulin with IC50 concentrations of 23.1, 53.4, and 91.0 nM, respectively. Since it is believed that a progestin may exert androgenic effects by displacing testosterone from sex hormone-binding globulin, thereby increasing circulating levels of free, active testosterone, these data are consistent with the results of preclinical and clinical studies demonstrating the selective progestational activity of norgestimate.