Figure 1. Immunohistochemical localization of uterine serpin in endometrial glands of an ovariectomized ewe treated with progesterone for 60 days.
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These same results have not been seen in laboratory counterparts. Adult female rats that have been ovariectomized, a parallel state to menopause, show increased seizure frequency overall. There are, however, several factors that could explain this difference, including ovariectomized rats do not have the analogous brain hormones milieu as menopausal women. Several studies following HRT use in women with catamenial epilepsy have demonstrated more influencable data than animal models, in this case.
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Klump et al. Progesterone may moderate the effects of low estradiol (such as during dysregulated eating behavior), but that this may only be true in women who have had clinically diagnosed binge episodes (BEs). Dysregulated eating is more strongly associated with such ovarian hormones in women with BEs than in women without BEs. The implantation of 17β-estradiol pellets in ovariectomized mice significantly reduced binge eating behaviors and injections of GLP-1 in ovariectomized mice decreased binge-eating behaviors.
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Studies have shown that coumestrol has beneficial properties on carbohydrate metabolism in ovariectomized rats, decreasing glycogen levels in skeletal muscle. There is also data indicating that coumestrol lowers plasma cholesterol levels in chicks. These results point to a possibility of coumestrol having a positive role to play against human obesity and diabetes in the future.
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The GnRH neurons are regulated by many different afferent neurons, using several different transmitters (including norepinephrine, GABA, glutamate). For instance, dopamine appears to stimulate LH release (through GnRH) in estrogen-progesterone-primed females; dopamine may inhibit LH release in ovariectomized females. Kisspeptin appears to be an important regulator of GnRH release. GnRH release can also be regulated by estrogen.
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In addition, some vitamin D derivatives have been known to inhibit the serum parathyroid hormone. Eldecalcitol only weakly inhibits the serum parathyroid hormone, making it an even more appealing medicinal drug for its physiological uses in the treatment of osteoporosis. Animal studies of eldecalcitol, in ovariectomized rats, show improvements in bone mass while lowering bone reabsorption to demonstrate its effectiveness in osteoporosis treatment.
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Results demonstrate that rats in this behavioral estrous show less impulsive burying and also less freezing behavior than diestrous rats. The authors then administered progesterone and estrogen in ovariectomized rats and tested them in marble burying and conditioned fear. The results for this experiment demonstrate that administration of progesterone or both estrogen and progesterone decreases impulsive burying. Both demonstrate a decrease in freezing behavior.
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Estradiol decanoate (E2D), or estradiol decylate, also known as estradiol 17β-decanoate, is a synthetic steroidal estrogen and an estrogen ester – specifically, the 17β-decanoate (decylate) ester of estradiol – which was studied for use in hormone replacement therapy for ovariectomized women in the late 1970s but was never marketed. Oral estradiol decanoate in oil at a dosage of 0.25 to 0.5 mg/day for 14 days has been studied in ovariectomized women and found to produce levels of estrone and estradiol with a ratio of about 1:2 (0.5) to 1:1.7 (0.6). This is in contrast to oral micronized estradiol, which has an estrone to estradiol ratio of about 5:1 (an 8- to 10-fold difference in ratio relative to oral estradiol decanoate in oil). The normal ratio of estrone to estradiol in women is about 1:2 (0.5) in premenopausal women and about 2:1 in postmenopausal women.
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An ovariectomized rat (OVX) is a female rat whose ovaries have been removed. Currently there is no single animal model that identically represents the stages of osteoporosis in humans although there are some animals that are relatively close and can be used for the purpose of comparison. Both small animals and large animals are used depending on which aspects of the osteoporotic condition are being studied. Such animals include rats, rabbits, and sheep.
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It has been shown to prevent the loss of tensile strength in human hair; to have a positive effect on the surface and mechanical properties of skin, and on the brittleness of hair and nails; to abate brittle nail syndrome; to partially prevent femoral bone loss in aged ovariectomized rats; to increase the concentration of collagen in calves; and to have a potentially beneficial effect on the formation of collagen in the bones of osteopenic women.
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Abaloropatide was known as BIM-44058 when it was first discovered at Ipsen and as BA058 while under development. The anabolic effects of abaloparatide on bone were demonstrated in two preclinical studies conducted in ovariectomized rats. Both studies showed increased cortical and trabecular bone volume and density, and trabecular microarchitecture improvement in vertebral and nonvertebral bones after short-term and long-term daily subcutaneous injection of abaloparatide compared to controls. Recent studies indicated a dose-dependent increased in bone mass and strength in long-term abalorapatide treatment.
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Rosenblatt's 1967 study of the induction of maternal behavior is consider by many in his field to be his most famous study. In that study he showed that the neural basis of parental care is independent of pregnancy and birth. He found that he could induce maternal behavior in virgin female rats during a 6 to 8 day period by continuously exposing them to rat pups. He also found that female rats that were ovariectomized or hypophysectomized could also be induced to exhibit maternal behavior via the continuous exposure to rat pups.
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Preclinical trials were performed in ovariectomized rats to model menopause. Oral ospemifene was compared with raloxifene (another SERM), its metabolites 4-hydroxy ospemifene and 4'-hydroxy ospemifene, estradiol, and ospemifene administered as an intravaginal suppository. Estradiol was used as a positive control and raloxifene was used because it is in the same drug class as ospemifene. Multiple doses of oral ospemifene were tested. 10 mg/kg/day of Ospemifene was found to cause a greater increase in vaginal weight and vaginal epithelial height than 10 mg/kg/day of raloxifene.
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A study published in Chemical Research in Toxicology shows that 4-hexylresorcinol used as a food additive (E-586) exhibits some estrogenic activity, i.e. resembles action of the female sex hormone estrogen. However, recent study published in Applied Sciences shows that 4-hexylresorcinol did not change the expression of estrogen receptor-α, -β, or p-ERK1/2 in MCF-7 cells. In an ovariectomized animal model, the 4HR group showed similar levels of ERα, ERβ, and prolactin expression in the pituitary gland compared to the solvent only group, while the estradiol group showed higher levels.
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Sex hormones play an important role in the regulation of TRPV6. In comparison to male mice, female mice exhibit a 2-fold higher increase in duodenal expression of TRPV6 mRNA following vitamin D treatment. Sex hormone-associated differential regulation of TRPV6 across genders is believed to be correlated to differences in relative risk to osteoporosis in older postmenopausal women which have been reported to have lower TRPV6 and VDR expression in comparison to males. Estrogen treatment upregulates TRPV6 transcripts by 8-fold in VDR KO mice and by 4-fold in ovariectomized mice.
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Indeed, it has been shown in ovariectomized chimpanzees that swelling can be induced by estrogen and inhibited by progesterone. As a result, the peak size of the swellings often coincides with the highest potential of ovulation, although this is not a perfect association. For example, research on West African chimpanzees showed that higher probabilities of ovulation tended to occur within 7 to 9 days of the onset of maximum swelling of sexual skin. Additionally, a study into wild white-handed gibbons showed that maximum swelling size and ovulation overlapped closely in 80% of menstrual cycles.
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Conversely, the progesterone-like effects of amphenone B on the mammary glands were found to persist even in adrenalectomized and ovariectomized animals. Amphenone B was tested in humans in the mid-1950s as a potential treatment for cortisol-dependent conditions such as Cushing's syndrome and adrenocortical carcinoma. In healthy subjects and patients with adrenocortical carcinoma, the drug was found to be effective in decreasing circulating levels of corticosteroids including cortisol, corticosterone, and aldosterone, as well as in decreasing circulating levels of androgens and estrogens. Moreover, due to reduced aldosterone secretion, it caused marked diuresis and increased urinary sodium excretion.
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The structure and activity relationship of toremifene is similar to that of tamoxifen, but it has a substantial improvement from the older drug in regards to DNA alkylation. The presence of the added chlorine atom reduces the stability of cations formed from activated allylic metabolites and thus decreases alkylation potential, and indeed toremifene does not display DNA adduct formation in rodent hepatocytes. Toremifene protects against bone loss in ovariectomized rat models and affects bone resorption markers clinically in a similar fashion to tamoxifen. Toremifene undergoes phase I metabolism by microsomal cytochrome P450 enzymes, like tamoxifen, but primarily by the CYP3A4 isoform.
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Females are known to practice oviposition, with preference for high moisture soils, with water saturation greater than 70%. Female clutch sizes are 100-200 eggs, with at least one clutch laid per female. In experimental studies with ovariectomized female mosquitoes, females were unable to synthesize vitellogenin, a yolk-protein precursor, unless given a donor ovary from a sugar-fed or blood-fed mosquito. Vitellogenin synthesis still occurred when the donor ovary came from Ae. aegypti, and ovary derivation from a blood-fed mosquito caused corpus cardiacum stimulating factor production, indicating that the hormonal processes for oviposition are not species specific.
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While the primary cause of the end to menstrual cycles is the exhaustion of ovarian follicles, there is some evidence that a defect in the hypothalamus is critical in the transition from regular to irregular cycles. This is supported by at least one study in which transplantation of ovaries from old rats to young ovariectomized rats resulted in follicular development and ovulation. Also, electrical stimulation of the hypothalamus is capable of restoring reproductive function in aged animals. Due to the complex interrelationship among the hypothalamus, pituitary and ovaries (HPO axis) defects in the functioning of one level can cause defects on the other levels.
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Toxicological issues prevented long term use of clomifene and further drug development for other potential applications such as breast cancer treatment and prevention. Figure 1: Timeline of when SERMs came on the market. It was another ten years before tamoxifen was approved in December 1977, not as a contraceptive but as a hormonal treatment to treat and prevent breast cancer. The discovery in 1987 that the SERMs tamoxifen and raloxifene, then thought to be antiestrogens because of antagonist effects in breast tissue, showed estrogenic effects in preventing bone loss in ovariectomized rats had a great effect on our understanding of the function of estrogen receptors and nuclear receptors in general.
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In clinical research in the 1930s, estrone was given via intramuscular injection to ovariectomized women in order to study its effects and to elucidate the biological properties of estrogens in humans. In these studies, prior to administration of estrone, amenorrhea, atrophy of the breasts (as well as flaccidity and small and non-erectile nipples), vagina, and endometrium, vaginal dryness, and subjective symptoms of ovariectomy (e.g., hot flashes, mood changes) were all present in the women. Treatment with estrone was found to dose- and time-dependently produce a variety of effects, including breast changes, reproductive tract changes of the vagina, cervix, and endometrium/uterus, and relief from the subjective symptoms of ovariectomy, as well as increased libido.
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Estradiol cyclooctyl acetate (E2COA), or estradiol 17β-cyclooctylacetate, also known as estra-1,3,5(10)-triene-3,17β-diol 17β-cyclooctylacetate, is an estrogen medication and an estrogen ester – specifically, the 17β-cyclooctylacetate ester of estradiol – which has been studied for use in hormone replacement therapy for ovariectomized women and as a hormonal contraceptive in combination with a progestin but was never marketed. It has greater oral bioavailability than does micronized estradiol due to absorption via the lymphatic system and hence partial bypassing of first-pass metabolism. It is approximately twice as potent as micronized estradiol orally and has a comparatively reduced impact on liver parameters such as changes in sex hormone-binding globulin production. It was investigated in combination with desogestrel as a birth control pill, but resulted in unacceptable menstrual bleeding patterns and was not further developed.
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In contrast to p,p'-DDD, which has direct cytotoxic effects on the adrenal glands via an unknown mechanism, amphenone B does not have cytotoxic effects, and instead causes adrenal and thyroid gland hypertrophy due to respective inhibition of corticosteroid and thyroxine biosynthesis, subsequent loss of negative feedback on the hypothalamic-pituitary-adrenal and hypothalamic-pituitary- thyroid axes, and consequent hypersecretion of adrenocorticotropic hormone (ACTH) and thyroid-stimulating hormone (TSH) from the pituitary gland. Amphenone B has also been found to produce progesterone-like progestogenic effects, including uterine hypertrophy and mammary lobuloalveolar development. These effects occurred even in animals that had been ovariectomized and hypophysectomized, suggesting that amphenone B might be acting directly on the target organs. However, it was found that adrenalectomy abolished the progesterone-like effects of amphenone B on the uterus, whereas those of progesterone were retained in the same experimental conditions, supporting the notion that amphenone B was not actually acting directly on the uterus.
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