Histological changes in the ovary and uterus of rat after injectable contraceptive therapy.
TL;DR: The whole morphological alteration in the ovary after DMPA therapy appeared to be the atresia of the follicular apparatus with degeneration of the growing follicles.
Abstract: Histological changes were studied in the ovary and uterus of rats receiving different doses of Depo-Provera (DMPA) and Noristerat (NET-EN) for varying duration. The effect of DMPA on ovarian and uterine tissues was strongly progestational. The whole morphological alteration in the ovary after DMPA therapy appeared to be the atresia of the follicular apparatus with degeneration of the growing follicles. Uterine histology reflected that endometrial tissues gradually became inactive and with prolonged treatment at high doses, atrophy of the endometrium was noted. In NET-EN-treated rats, absence of mature follicles and recent corpora lutea reflected the blockade of ovulation. There was no extreme atrophy of the ovary or endometrium as found with DMPA treatment. With higher doses of NET-EN, endometrial growth was arrested.
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TL;DR: Findings suggest that M PA treatment leads to long-lasting cognitive impairments in the rodent, even in the absence of circulating MPA in animals given prior MPA treatment, which may relate to the GABAergic system.
Abstract: Rationale
The synthetic progestin medroxyprogesterone acetate (MPA), widely used in hormone therapy (HT) and as the contraceptive Depo Provera, is implicated in detrimental cognitive effects in women. Recent evidence in aged ovariectomized (Ovx) rodents shows that short-term MPA treatment impairs cognition and alters the GABAergic system.
51 citations
Cites background or methods from "Histological changes in the ovary a..."
...This regimen of MPA treatment was selected based on previously established anti-ovulatory effects (Bhowmik and Mukherjea 1988) in order to mimic the biological action of Depo Provera taken by women (Depo Provera Prescribing Information 2006)....
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...Although it has previously been shown by Bhowmik and Mukherjea (1988) that weekly injections of 3.5 mg of MPA are sufficient to halt ovulation for at least 7 days, we confirmed this in a pilot study with animals, not included in Visible Platform behavioral testing, at 3 months of age and of the…...
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TL;DR: Encapsulation of ethinylestradiol in ultraflexible liposomes modified the pharmacodynamics and pharmacokinetics of the contraceptive agent, resulting in a marked improvement in bioavailability and optimized therapy.
Abstract: This study aimed to develop ultraflexible liposomes as an alternative to the oral route, which would enhance the bioavailability and reduce the toxicity of ethinylestradiol. Ultraflexible liposomes of ethinylestradiol using an optimized concentration of surfactants were prepared and characterized in vitro. The effect of surfactant type under non-occlusive conditions on transdermal permeability was assessed. A histopathological study was performed to assess the action of ethinylestradiol on the uterus and ovaries. The pharmacokinetics of free ethinylestradiol (following single oral administration and one day of application to the skin), ultraflexible liposomal ethinylestradiol and non-flexible liposomal ethinylestradiol were studied in female Sprague-Dawley rats. Insignificant differences in size between the ultraflexible liposomal formulations containing optimized concentrations of different surfactants were observed. Ultraflexible liposomes can penetrate through pores much smaller than their own diameter. The transdermal permeability of lipophilic surfactant was greater than that of hydrophilic surfactant. The release of ethinylestradiol from the proposed formulation through rat skin was found to be constant. The histopathological study showed that the ultraflexible liposomal transdermal drug delivery system for ethinylestradiol provided effective contraception by follicular cell lysis, depletion of zona granulosa and ova, and by increasing the uterine mucosal and endometrial proliferation. Encapsulation of ethinylestradiol in ultraflexible liposomes modified the pharmacodynamics and pharmacokinetics of the contraceptive agent, resulting in a marked improvement in bioavailability and optimized therapy.
29 citations
Cites background from "Histological changes in the ovary a..."
...The high flux rate has been attributed to naturally occurring transdermal osmotic gradients (Bhowmik & Mukherjea 1988)....
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...The morphological changes produced by the direct action on the uterine endometrium of the rats were recorded (Bhowmik & Mukherjea 1988; Thompson 1990)....
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TL;DR: In normal mammary gland of female rats: progestin action depends on estrogen presence and MPA does not revert estrogen-dependent proliferation, but it magnifies estradiol effect.
Abstract: Objective: The purpose of this study was to evaluate the effects of two sex hormones on normal mammary gland of female rats. Methods: Forty 250-day-old female rats, 20 of them with offspring and 20 not, were ovariectomized and, divided into 4 subgroups in order to receive one of the following subcutaneous treatment: estradiol benzoate (EB), medroxyprogesterone (MPA), EB + MPA or placebo, for 10 weeks. After treatment, mammary glands were studied with optical microscope. Whole gland, lobule, ductule and lumen compartments were evaluated by morphometric methods. Also a qualitative evaluation were performed seeking for secretion, microcalcification and trophic status. Results: It was found that (a) MPA-only and placebo were similar for all parameters; (b) the same between EB and EB + MPA; (c) EB and EB + MPA increased lobule, ductule and lumen compartments significantly compared to MPA-only or placebo; (d) EB increased epithelium but without significance and EB + MPA increased it significantly compared to placebo or MPA; (e) EB and EB + MPA incremented secretion. Conclusions: In normal mammary gland of female rats: progestin action depends on estrogen presence. MPA does not revert estrogen-dependent proliferation, but it magnifies estradiol effect. Both EB and EB + MPA stimulate differentiation. Rats without offspring presented a greater epithelial proliferation under treatment with these sex hormones.
22 citations
14 Aug 2018
TL;DR: In this article, the authors provided more information on normal anatomy, histology, physiology, and endocrinology of Reproductive System and Mammary Gland, and discussed compound-related effects on the reproductive system can be pivotal in pharmaceutical development.
Abstract: This chapter provides more information on normal anatomy, histology, physiology, and endocrinology of Reproductive System and Mammary Gland. Compound-related effects on the reproductive system can be pivotal in pharmaceutical development. It considers the male and female reproductive systems together with the mammary gland as many basic concepts track across these organ systems. Embryological development of the reproductive tract is broadly similar species but there are detailed differences, particularly in the timing of events. The development of xenobiotic-induced endometrial hyperplasia in rodents has been reported in numerous studies of animals exposed in utero, prepubertally, or after ovariectomy. Postnatal testicular development varies among species, just as the timing of puberty varies. The term "puberty" denotes the time period encompassing hormonal changes, development of sexually dimorphic traits, and the achievement of fertility. Considerable confusion exists regarding the terminology of sexual maturation.
17 citations
TL;DR: These results confirm the potential of these mucoadhesive vaginal tablets to enhance P4 efficacy and avoid the side effects associated with IM injection.
Abstract: Objective: To develop mucoadhesive tablets for the vaginal delivery of progesterone (P4) to overcome its low oral bioavailability resulting from drug hydrophobicity and extensive hepatic metabolism.Methods: The tablets were prepared using mixtures of P4/Pluronic® F-127 solid dispersion and different mucoadhesive polymers. The tablets physical properties, swelling index, mucoadhesion and drug release kinetics were evaluated. P4 pharmacokinetic and pharmacodynamic properties were evaluated in female rabbits and compared with vaginal micronized P4 tablets and intramuscular (IM) P4 injection, respectively.Results: The tablets had satisfactory physical properties and their swelling, in vitro mucoadhesion force and ex vivo mucoadhesion time were dependent on tablet composition. Highest swelling index and mucoadhesion time were detected for tablets containing 20% chitosan-10% alginate mixture. Most tablets exhibited burst release (∼25%) during the first 2 h but sustained the drug release for ∼48 h. In vi...
12 citations
Cites background from "Histological changes in the ovary a..."
...Further, the uterus in rabbits administrated F12 tablets showed atrophy of epithelium of endometrial glands, probably due to local effect of high P4 concentration (Figure S1, Supporting information) [57]....
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References
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TL;DR: It is indicated that medroxyprogesterone acetate administered in this dosage acts as a contraceptive by inhibiting release of LH.
Abstract: In order to determine the mechanism whereby intramuscular injection of a long-acting medroxyprogesterone inhibits ovulation, daily immunoassay of urinary excretion of LH was performed on 4 subjects. During two control cycles prior to treatment, a midcycle peak of LH excretion was observed at the approximate time of ovulation in all subjects. After treatment with 150 mg. of Depo-Provera, there was no peak of LH excretion observed in any subject during the time the drug was active. In the two subjects who had assays continued until ovulation resumed, there was again evidence of a peak in LH excretion at the time of ovulation. This study indicates that medroxyprogesterone acetate administered in this dosage acts as a contraceptive by inhibiting release of LH.
32 citations
TL;DR: Intramuscular injections of an oily suspension of 200 mg of norethisterone enanthate were given to 130 young fertile healthy women at 3-month intervals; most were treated for more than a year with the average 17.6 months.
Abstract: Intramuscular injections of an oily suspension of 200 mg of norethisterone enanthate were given to 130 young fertile healthy women at 3-month intervals; most were treated for more than a year with the average 17.6 months. 46 began the injections within 30 days postpartum. Physical and pelvic examinations and a Papanicolaou smear were performed at the beginning and repeated every 12 months. Amenorrhea or irregular uterine bleeding were the most troublesome side effects and the most frequent cause for the 25% dropout rate. Accessory oral estrogens were added for 5-7 days of each month to relieve these symptoms. On a selected group vaginal cytology cervical mucus and Huhner-Sims postcoital tests were done along with an endometrial biopsy and urinary pregnanediol excretion studies. Changes in cervical mucus interfering with sperm survival and ascent were noted. The endometrial histology was normal in 17 biopsies with iatrogenic changes in 64 specimens. There were 3 pregnancies 2.3% in 2300 treated months. No major changes were observed in libido or orgasm. The inhibition of fertility is rapidly reversible upon discontinuing therapy. In 5 or 6 women undergoing laparotomy while in therapy no signs of ovulation or corpus luteum formation were found. In one operated on during the fourth month after the last injection a recent corpus luteum was found.
30 citations
TL;DR: The contraceptive efficacy and menstrual abnormalities of long-acting medroxyprogesterone acetate, injected intramuscularly at doses of 150 mg every 3 months for 1 year, were studied in 14 women, finding the chief advantage is the infrequent need for injection.
Abstract: Present means of contraception are not satisfactory for all women. This study reports on the contraception efficacy and menstrual abnormalities of medroxyprogesterone acetate (Depo-Provera), which was given in an intramuscular dose of 150 mg. every 3 months for 1 year. None of the 14 patients who received the full 12 months of therapy became pregnant. The occurrence of spotting and bleeding was erratic, but each tended to decrease as the treatment continued. After cessation of treatment, most patients had two or three “normal menstrual periods,” which biopsy proved to be from a proliferative endometrium. All patients had a secretory endometriurn within 12 months after the last injection, or within 9 months after the effects of the last injection had presumably worn off. Irregular bleeding, spotting, and relatively prolonged anovulation are the main disadvantages of this form of therapy. The chief advantage is the infrequent need for injection; patients need to be concerned with birth control only 1 day every 3 months.
25 citations
Journal Article•
TL;DR: There was no change in the endometrial or cytological picture after several years of treatment and at no time was evidence of hyperestrogenic alteration found.
Abstract: Endometrial histology and vaginal cytology during oral contraception with sequential estrogen and progestin were studied. 355 endometrial biopsies and 168 Papanicolaou smears were obtained during the course of 2876 cycles of oral contraception over a period of 27 months in 317 women. Sequential therapy (20 days of mestranol at 80 mcg per day with 2 mg chlormadinone acetate per day added during the last 5 days) was used. This method differs in several fundamental aspects from the current types or oral contraceptives based on 20 day administration of an estrogen-progestin combination. In contrast to the latter form of therapy which produces a regressive or atrophic type of endometrium sequential therapy yields a vaginal cytology and endometrial pattern closely resembling that of the normal menstrual cycle corresponding to the picture of Cycle Day 19 at the completion of a course of treatment. The only difference from normal endometrial histology was the greater frequency and intensity of stromal edema in some treated endometria. There was no change in the endometrial or cytological picture after several years of treatment and at no time was evidence of hyperestrogenic alteration found. Vaginal cytology responded more rapidly and more intensely to the hormonal stimuli than did the endometrium.
23 citations
TL;DR: It is possible that map suppresses the synthesis or the release of luteinizing hormone (lh) from the pituitary gland and thus prevents the production of sufficient endogenous oestrogen to cause implantation.
Abstract: Intact, female Holtzman rats were treated daily with medroxyprogesterone acetate (map; Provera) in corn oil, beginning on the day of insemination. This caused delay of implantation in 14% (0\m=.\5mg/day) to 100% (2\m=.\4mg/day) of the animals tested. It is possible that map suppresses the synthesis or the release of luteinizing hormone (lh) from the pituitary gland and thus prevents the production of sufficient endogenous oestrogen to cause implantation. Implantation was achieved in 'delayed' rats by simultaneous administration of 1 \g=m\gof oestrone with the dose of map they had been receiving. The viability of foetuses in such animals varied inversely with the dose of map the mothers had received.
16 citations