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Effects of medroxyprogesterone acetate on socio-sexual behavior of stumptail macaques.

Two studies assessed (1) the effect of medroxyprogesterone acetate (MPA), Depo-Provera, on socio-sexual behaviors, and (2) the interaction between socio-environmental conditions and MPA treatment effects. Study One utilized two males and eight female members of a semi-free-ranging island colony. Females received 30 or 100 MPA IM or were untreated. Study Two used three laboratory-housed pairs of tubal-ligated females, observed during 30 min behavior tests with one of three males. Sexually preferred females received 30 mg MPA IM. Semi-free-ranging treated females received fewer ejaculations than untreated females and did not copulate for up to 68 days post-treatment. Rates of grooming were not affected. In the laboratory tests, mean rates of ejaculations per test were reduced for treated females but increased for untreated females, and untreated females groomed males more than did treated females. Contrary to previous studies, these results suggest that stumptail macaque sexual behavior can be influenced by hormones but this influence is modulated by socio-environmental factors.

Animals↗

Effects of medroxyprogesterone acetate on plasma testosterone and sexual behavior in male cynomolgus monkeys (Macaca fascicularis).

Medroxyprogesterone acetate (MPA), a synthetic progestin with androgen-depleting activity, is used to treat the deviant sexual behavior of men. To investigate the effects of MPA in another anthropoid primate, 16 oppositely-sexed pairs of cynomolgus monkeys were observed in one-hour behavior tests during 15 successive 4-week periods conducted before, during and after administering to males weekly IM injections of first 20 mg and then 40 mg MPA. The doses used were comparable on a body weight basis to those employed clinically. Blood samples were collected weekly and assayed for plasma testosterone. During MPA treatment both plasma testosterone and ejaculatory behavior were significantly decreased, but the changes in behavior were less marked than the changes in hormone levels. There were clear differences between individual males in the effects of treatment, and the identity and hormonal status of the female partners also influenced the results. During the 6 month withdrawal period, effects were only partially reversible, and the data suggested that the behavioral changes depended on the hormonal changes rather than the opposite. However, a direct central action of MPA on behavioral mechanisms could not be excluded.

Animals↗

Effects of domperidone and medroxyprogesterone acetate on ventilation in man.

If endogenous dopamine acts as an inhibitory neurotransmitter in the carotid bodies in man, domperidone (DP), a selective dopamine D-2 receptor antagonist should stimulate carotid bodies and augment ventilation. Furthermore, the combination of a central ventilatory stimulant, medroxyprogesterone acetate (MPA), with a peripheral ventilatory stimulant, DP, may produce an additive/synergistic ventilatory effect. We conducted a double-blind, placebo-controlled (P), cross-over trial comparing MPA 20 mg three times daily (TID) and DP (20 mg TID) alone and together in 8 healthy male human subjects. Drug effects were measured after 7 days, and a two-week drug washout period was allowed. MPA significantly increased alveolar ventilation (VA), and slopes of hypercapnic and hypoxic ventilatory responses. Domperidone alone significantly increased the slope of the hypoxic response; however, VA and PaCO2 did not change significantly. The combination of MPA and DP resulted in ventilatory changes similar to MPA alone. We conclude that in man endogenous dopamine acts as a modulator of chemoreception during hypoxemia, but plays no major role tonically in control of ventilation during normoxemia and normocapnia. Lack of additive effect with combined DP and MPA suggests that these drugs may share the same final common pathway in the process of chemoreception.

Adult↗

In vitro metabolism of progestins. III. The metabolic clearance rate of medroxyprogesterone acetate in monkeys.

3H-medroxyprogesterone acetate (MPA) was synthesized by selective catalytic tritiation of the delta1-olefinic bond of 6alpha-methyl-17alpha-hydroxy-pregna-1,4-diene-3,20-dione acetate. The metabolic clearance rate of MPA (MCRMPA) was determined in 9 female Rhesus monkeys by the single injection technique. The blood MCRMPA was 201 +/- 19 L/day (42.2 +/- 4.0 L/day/kg) which was approximately the same as that reported for progesterone clearance in the monkey. We conclude that a greater biological activity of MPA compared to progesterone cannot be related to its prolonged retention in the blood. Although both MPA and amino-glutethimide alter the rate of steroid metabolism in some species, neither of these agents influences the metabolic clearance rate of 3H-MPA in the monkey.

Aminoglutethimide↗

Role of monoamine oxidase-B in medroxyprogesterone acetate (17-acetoxy-6 alpha-methyl-4-pregnene-3, 20-dione) induced changes in brain dopamine levels of rats.

The effect of medroxyprogesterone acetate (MPA) on brain monoamine levels and monoamine oxidase (MAO) activity was studied in adult, healthy, non-pregnant female rats. MpA was injected in a single dose of 100 mg/kg i.m. Dopamine (DA), noradrenaline (NA), 5-hydroxytryptamine (5-HT) levels and MAO activity were estimated fluorometrically in rat brian. No change in DA, NA, 5-HT or MAO activity was observed after 7 days of MPA treatment while a significant decrease in DA levels along with a significant increase in MAO activity was observed after 21 days of MPA treatment. However, there was no change in NA and 5-HT levels after 21 days of MPA administration. The selective reduction of DA by MPA could be due to an increase in MAO-B activity. MPA does not appear to increase MAO-A activity because neither of the specific substrates (NA and 5-HT) of MAO-A was found to be decreased inspite of the increase in MAO activity as estimated by the kynuramine method. These findings suggest the importance of MAO-B also in DA metabolism in rat brain.

Animals↗

Differential responses of rabbit endocervix and uterus to medroxyprogesterone acetate.

Uteri and cervices were obtained from estrous rabbits (controls) and from rabbits 24 h or 7 days after a single intramuscular injection of medroxyprogesterone acetate (MPA; 2.14 mg/kg). Estrogen and progesterone receptor concentrations were measured by Scatchard analysis, cell-free DNA synthesis was measured by (3H)-TTP incorporation, and tissue sections were examined histologically. The uterine endometrium underwent marked changes in histology, including extensive infoldings of the mucosal surface, glands were continuous into crypts and secretory epithelial cells were noted. In addition, total estrogen receptor content and DNA synthesis were decreased. In contrast, there was no significant change in the histology of the endocervical epithelial-stromal complex, and total estrogen receptor remained constant. However, DNA synthesis in the endocervix was decreased. Thus we conclude that: DNA synthesis is not linked to changes in estrogen receptor in the endocervix; and differential effects of progestogen on the estrogen receptor system occur coincident with different morphological responses within two target tissues from the same animal.

Animals↗

Short- and long-term effects of hormone replacement therapy (transdermal estradiol vs oral conjugated equine estrogens, combined with medroxyprogesterone acetate) on blood coagulation factors in postmenopausal women.

We compared the effects on hemostatic variables of transdermal estradiol and oral equine conjugated estrogens (CEE), both combined with medroxyprogesterone acetate, in 40 postmenopausal women, 22 randomly allocated to transdermal estradiol and 18 to CEE. Antithrombin III (AtIII), fibrinogen, factor VII, factor VIII and tissue plasminogen activator before and after venous stasis were measured at the start of therapy and after two and four months in all patients, and after 12 months in a subgroup of 21 patients (12 from the estradiol and nine from the CEE group). In the short-term study (two and four months), analysis of variance did not reveal any significant difference between treatments for any of the hemostatic variables. A significant treatment by time interaction was found only for fibrinogen levels: at two months they were significantly higher in the estradiol group. In the long-term study (12 months), a significant decrease in AtIII and a significant increase in factor VIII were observed in both groups, without differences between treatments. The clinical relevance of the observed changes is doubtful, but nevertheless they should be considered in a more extensive evaluation of the potential cardiovascular risk and benefits of hormone use.

Administration, Cutaneous↗

Endocrine manipulation of meningiomas with medroxyprogesterone acetate. Effect of MPA on receptor status of meningioma cytosols.

Fifteen patients with intracranial or spinal meningiomas have been treated with the semisynthetic progestational agent medroxyprogesterone acetate (MPA, Depo-Provera) prior to surgical removal of the tumors in order to investigate the influence of MPA on the progesterone receptor (PR) status of meningioma cytosols. MPA acted as a competitive binder to meningioma-PR: The mean PR values were 15.6 fmol/mg protein (range 0-69) and 338.3 fmol/g tumor (range 0-1190), respectively. In comparison, mean PR values of our untreated meningioma series (n = 58) were 54.9 fmol/mg protein (range 0-586) and 2813 fmol/g tumor (range 0-17,168), respectively. In cases of two-stage resection of meningiomas MPA significantly decreased PR activity in the cytoplasm of meningioma cells. We conclude that MPA binds to meningioma PRs, however, its effect on the growth rate of meningiomas has still to be elucidated.

Cytosol↗

Endometrial carcinoma: steroid receptors and response to medroxyprogesterone acetate.

The steroid receptor content of the primary endometrial cancer of 22 patients who were treated for recurrent or advanced disease has been measured and correlated with response to medroxyprogesterone acetate. No patient with a progesterone receptor (PR)-negative tumor responded and only 2 patients with PR-positive tumors responded, perhaps related to the low levels of PR in the tumors. It waits to be assessed whether receptor status is as good a guide to response to hormone therapy as tumor differentiation, site of recurrence, or disease-free interval.

Adenocarcinoma↗

In vitro growth regulation of endometrial carcinoma cells by tamoxifen and medroxyprogesterone acetate.

The growth inhibitory effects of medroxyprogesterone acetate (MPA) and tamoxifen (TAM) were tested on three long-established endometrial carcinoma cell lines (HEC-1, KLE, and RL95-2) and on UM-EC-1, a new endometrial carcinoma cell line established in our laboratory. MPA and TAM were used in growth experiments either alone, simultaneously, or sequentially. The MCF-7 breast cancer cell line was used as a control. None of the endometrial carcinoma cell lines showed significant sensitivity to 0.1-10 microM MPA. In contrast, 10 days exposure to 5 microM TAM induced 83 and 70% growth inhibition in HEC-1 and KLE cultures, whereas the growth of UM-EC-1 was inhibited by 99.7% and RL95-2 cultures by 100%. TAM-induced growth inhibition was reversible since all cell lines resumed logarithmic growth when TAM was removed from the culture medium. Addition of 17 beta-estradiol (E2) to the culture medium did not accelerate recovery, and reversal of TAM-induced growth inhibition was not seen when TAM and E2 were added simultaneously. This is consistent with our finding that, except for MCF-7, these cell lines did not show detectable estrogen receptor (ER) activity in assays performed at the time of these experiments. When treated sequentially with TAM and MPA, all cell lines resumed logarithmic growth when medium containing TAM was replaced with medium containing MPA. Simultaneous exposure to 5 microM MPA and 5 microM TAM resulted in a slight additive growth inhibitory effects only in KLE cultures. Our results show that MPA does not have growth inhibitory effects in these endometrial carcinoma cell cultures, whereas TAM exerts a potent inhibitory effect that is not reversed by estrogen and may thus be mediated through a mechanism different from blockade of ER. In vitro results with the UM-EC-1 cell line correlated with the clinical response of the cell line donor. Her disease progressed during postoperative MPA therapy, but subsequently she responded to TAM therapy.

Aged↗

Medroxyprogesterone acetate and tamoxifen do not decrease aggressive behavior in CF-1 male mice.

Intact CF-1 male mice were given daily injections of either medroxyprogesterone acetate (MPA, an antiandrogen), tamoxifen (TAM, an antiestrogen), or the two drugs in combination and tested for aggressive behavior toward bulbectomized stimulus males. None of the treatments decreased fighting behavior over a 20-day test period and the presence of TAM led to increased aggression even in the presence of MPA. Testis weight was reduced by MPA while both compounds decreased seminal vesicle weight. The mechanisms involved in the observed effects are considered as well as the implications of the results for the clinical use of these compounds as modulators of testosterone-facilitated behaviors.

Aggression↗

Effects of medroxyprogesterone acetate on some parameters of calcium metabolism in patients with glucocorticoid-induced osteoporosis.

Long-acting medroxyprogesterone acetate (MPA) effect on some important parameters of calcium metabolism in patients with glucocorticoid-induced osteoporosis (GCO) was evaluated. Twelve steroid-dependent asthmatic male patients with GCO were administered 200 mg of MPA (Depo-Provera) intramuscularly, and had fasting serum samples obtained at baseline and at weekly intervals for 5 consecutive weeks. Baseline serum samples were also obtained from 12 control healthy male subjects matched for age. The following measurements were made from each serum sample: osteocalcin (OC), skeletal (SAP) and total alkaline phosphatase (TAP), calcitonin (C), insulin-like growth factor I (IGF1), 1,25-dihydroxyvitamin D and 25-hydroxyvitamin D. Significantly lower baseline serum levels of OC and C were found in the patients with GCO than in controls (P less than 0.001). Following MPA administration in GCO patients statistically significant and sustained increases in OC, SAP and C were noticed during the next 5 weeks. No significant differences in baseline levels for TAP, IGF1, 1,25(OH)2D and 25(OH)D between GCO patients and controls were found, and no significant changes following MPA administration in GCO patients were obtained for these parameters. In conclusion, when administered to patients with GCO, MPA seems to stimulate the osteoblastic activity as suggested by sustained increases in OC and SAP serum levels, and also enhances the C production by the C-cells of the thyroid.

Aged↗

Effect of medroxyprogesterone acetate on DMBA-induced rat mammary carcinoma and on immunological reactivity.

The antineoplastic activity of medroxyprogesterone acetate (MPA) was investigated in rats bearing DMBA-induced mammary carcinomas, a classical model of hormone-dependent tumor. Using a repeated injection schedule of relatively short duration, MPA was markedly effective (80% CR + PR) not only on relatively small (1-1.5 cm) tumors but also on advanced (4.5-5.5 cm) neoplasms. MPA effectiveness was comparable to that of a frankly toxic adriamycin regimen. In antitumorally effective schedules MPA was incapable of significantly affecting in either direction cellular and humoral immunological reactivities in rodents.

9,10-Dimethyl-1,2-benzanthracene↗

Combined and sequential treatment using FCE 21336, a new prolactin-lowering drug, and medroxyprogesterone acetate (MPA) in DMBA-induced tumors in rats.

The effect of the new, prolactin-lowering ergoline derivative FCE21336 and medroxyprogesterone acetate (MPA) given alone and in combination was tested on DMBA-induced mammary tumors in rats. FCE 21336 (0.05 and 0.4 mg/kg p.o.) and MPA (25 and 50 mg/kg s.c.), administered 5 days/week for 4 weeks, inhibited the growth of established tumors and reduced serum prolactin levels. Combined treatment inhibited tumor growth more than single treatment. These results were confirmed in a second experiment: the antitumor effect of the combination of FCE 21336 (0.1 mg/kg p.o.) and MPA (50 mg/kg s.c.) was greater than that of the single treatment and was similar to the effect of ovariectomy. In this experiment rats with tumors that did not respond to 4 weeks' treatment with FCE 21336 (0.1 mg/kg p.o.) were treated during the next 4 weeks with MPA (50 mg/kg s.c.). MPA was effective on FCE 21336-unresponsive tumors. These data indicate that combined FCE 21336 and MPA treatment is more effective than single treatment and that MPA is effective on tumors not sensitive to the prolactin-lowering drug.

9,10-Dimethyl-1,2-benzanthracene↗

Medroxyprogesterone acetate and prednisone in advanced breast cancer. A randomized trial.

In a randomised trial patients with progressive metastatic breast cancer were allocated to one of three different treatments. A: Prednisone 10 mg X 3 daily. B: Medroxyprogesterone acetate (MPA) orally 500 mg daily. C: MPA i.m. 1000 mg daily for 3 weeks followed by 500 mg i.m. weekly. The study included 150 patients and was well-balanced with respect to different prognostic parameters. Most patients (83%) were postmenopausal, and 95% had previously received chemo- or hormonal therapy. In the MPA treated patients, analysis of serum MPA levels was performed once a month. The response rates were 4.6, 7.9 and 12.5% in treatments A, B and C, respectively. This difference was not statistically significant (P greater than 0.05). Furthermore, the follow-up of serum MPA levels revealed no significant difference between responders and non-responders. Analysis of time to progression did not indicate any advantage of MPA over prednisone, irrespective of MPA schedule. In accordance with these data, there was no difference as regards survival in the three groups. In conclusion, the study indicated that MPA is not superior to prednisone in this group of heavily pretreated patients with advanced breast cancer.

Administration, Oral↗

High-dose medroxyprogesterone acetate in combination with vindesine in advanced breast cancer.

Forty-three evaluable women with metastatic breast cancer received treatment with high-dose medroxyprogesterone acetate (MPA) plus vindesine. Patients tolerated treatment well, no lethal toxicities occurred. The commonest side-effects were hemopoietic, with leukopenia documented in 22 patients. Symptoms of peripheral neuritis occurred in 10 patients. A response rate of 28% (12 out of 43 patients) was seen. Ten of the responding patients had multiple prior chemotherapeutic agents. These results indicate that the combination of MPA and vindesine is not of value in patients with advanced breast cancer.

Adult↗

Additive inhibitory effects of bromocryptine (CB-154) and medroxyprogesterone acetate (MPA) on dimethylbenz[a]anthracene (DMBA)-induced mammary tumors in the rat.

Treatment for 18 days of rats bearing dimethylbenz[a]anthracene-induced mammary tumors with the synthetic medroxyprogesterone acetate (MPA) or the inhibitor of prolactin secretion 2 alpha-bromocryptine (CB-154) inhibited total tumor area to 30 +/- 7% of the original volume. Combination of the two drugs, on the other hand, caused further inhibition to 10 +/- 5% of the pretreatment tumor area. The most striking effect of combination of the two drugs is a doubling of complete responses (no detectable tumor) from 30% when either drug was used alone to 60% in animals treated with the combination therapy. Both estradiol and progesterone receptors were further decreased when MPA was added to CB-154. The present data demonstrate that combination of the synthetic progestin MPA and the inhibitor of prolactin secrection CB-154 exerts maximal inhibitory effects on the growth of the DMBA-induced mammary tumor, the most widely used in vivo model of human breast cancer.

9,10-Dimethyl-1,2-benzanthracene↗

Treatment of advanced endometrial adenocarcinoma with cyclic sequential ethinyl estradiol and medroxyprogesterone acetate.

Fifteen patients with recurrent or progressive endometrial adenocarcinoma of moderate to poor histologic differentiation were entered in a phase II trial of sequentially administered oral ethinyl estradiol and medroxyprogesterone acetate. There were no significant clinical responses in 12 patients evaluated for response and four patients experienced thromboembolic complications. This cyclic treatment regimen is considered ineffective for this patient population at the dosages and schedules used.

Adenocarcinoma↗