Prolactin is the primary LH in dogs and is required for sustenance of the corpus luteum,which produces progesterone. Prolactin synthesis by the pituitary gland is stimulatedindirectly by serotonin because serotonin inhibits dopamine, which is a direct inhibitorof prolactin. Therefore, increased levels of serotonin will block dopamine's ability toinhibit prolactin and prolactin levels will increase. Around day 25 to 30 of pregnancyafter the LH surge, prolactin levels significantly increase. When drugs that stimulatedopamine (dopamine agonists), such as bromocriptine or cabergoline, are administered tothe pregnant bitch during this prolactin increase, abortion occurs. The major limitationto use of these drugs is that they are less effective and require high dose administrationwhen used prior to day 40 of the pregnancy. Because inducing abortion in the pregnantbitch is not recommended after day 40, high-dose use of dopamine agonists has the effectof producing greater side-effects including vomiting and inappetence.
Normally the pituitary gland produces two hormones called FSH (Follicle Stimulating Hormone) and LH (Luteinizing Hormone). These hormones serve to stimulate the ovary to produce an egg each menstrual cycle (to ovulate). The ovary is also the production site for the woman’s two central female hormones: estradiol (EST), a type of estrogen, and progesterone (PRO), a type of progestin. BCPs are a combination of synthetic estrogen and progestin. BCPs "fool" the pituitary gland so that it produces less FSH and LH. By reducing the FSH and LH required for ovulation, BCPs suppress, but do not eliminate ovulation.
As the popularity of unopposed estrogen therapy waned, new approaches were sought. The focus was also directed away from the false claims of preserving feminine beauty and youthfulness and towards more urgent health matters. The pharmaceutical industry resurrected estrogen replacement therapy with the new 'safe' hormone replacement therapy - a combination of synthetic progesterone and estrogen which would supposedly protect menopausal women not only from cardiovascular disease but also from the ravages of osteoporosis.
McLean Estradiol-17ß Explanation Biological data Absorption, distribution, and elimination Biotransformation Hydroxylation Conjugation Biochemical parameters Synthesis Mechanism of action Toxicological studies Acute toxicity Short-term studies of toxicity Long-term studies of toxicity and carcinogenicity Genotoxicity Reproductive toxicity Special studies on mechanism of action Observations in humans Therapeutic use Estradiol-related genetic markers of carcinogenicity Progesterone Explanation Biological data Absorption, distribution, and excretion Biotransformation Biochemical parameters Synthesis Mechamism of action Toxicological studies Acute toxicity Short-term studies of toxicity Long-term studies of toxicity and carcinogencity Genotoxicity Reproductive toxicity Observations in humans Testosterone Explanation Biological data Absorption, distribution, and elimination Biotransformation Biochemical parameters Synthesis Mechamism of action Toxicological studies Acute toxicity Short-term studies of toxicity Long-term studies of toxicity and carcinogenicity Genotoxicity Reproductive toxicity Observations in humans Epidemiological studies of women exposed to postmenopausal estrogen therapy and hormonal contraceptives Methods Postmenopausal oestrogen therapy Exposure Human carcinogenicity Breast cancer Endometrial cancer Cervical cancer Ovarian cancer Cancers of the liver and biliary tract Colorectal cancer Cutaneous malignant melanoma Thyroid cancer Summary and conclusions Cardiovascular disease Osteoporosis Overall mortality Hormonal contraceptives Exposure Human carcinogenicity Breast cancer Endometrial cancer Cervical cancer Ovarian cancer Cancers of the liver and biliary tract Colorectal cancer Cutaneous malignant melanoma Thyroid cancer Summary and conclusions Cardiovascular disease Acute myocardial infarct Stroke Venous thromboembolism Overall mortality Meat intake and cancer risk Comments and evaluation Estradiol-17ß Progesterone Testosterone References The purpose of this monograph is to provide a review and summary of the scientific information relative to a toxicological assessment of the safety of three endogenous hormones, estradiol-17ß, progesterone, and testosterone, with emphasis on information published since the review of the Committee at its thirty-second meeting (Annex 1, reference 80).
As was previously mentioned, it is progesterone that is responsible for maintaining the secretory endometrium which is necessary for the survival of the embryo as well as the developing fetus throughout gestation. It is little realized, however, that progesterone is the mother of all hormones. Progesterone is the important precursor in the biosynthesis of adrenal corticosteroids (hormones that protect against stress) and of all sex hormones (testosterone and estrogen). This means that progesterone has the capacity to be turned into other hormones further down the pathways as and when the body needs them. The point needs to be emphasized that estrogen and testosterone are end metabolic products made from progesterone. Without adequate progesterone, estrogen and testosterone will not be sufficiently available to the body. Besides being a precursor to sex hormones, progesterone also facilitates many other important, intrinsic physiological functions (which will be discussed later).
hCG is a form of glycoprotein that is synthesised within the trophoblast cells of a . hCG is particularly important in primate reproduction where it has a similar effect to LH in stimulating the continued production of progesterone and oestrogens. This represents part of the system involved in foetal-maternal communication and . Primate blastocysts therefore produce hCG in relatively high concentrations during the first 3 months of pregnancy. hCG has also been suggested to play a role in defence of the embryo from the maternal immune system during the initial stages of pregnancy. In males hCG increases the growth of the foetal testes.
As hCG is only produced by embryonic cells, the presence of this hormone within maternal blood can be used for pregnancy confirmation.
Estradiol (E2) is a steroid hormone and is part of the oestrogens group of hormones and is the principle oestrogen in females. Estrone and estriol are chemically similar to estradiol but are found in lower concentrations and have a lower estrogenic activity. Production of oestrogens occurs in the ovary via , the and the Zona reticularis of the . In males in it is produced in sertoli cells found in the testes. Estradiol is synthesised from cholestrol.
Oestrogens have a number of functions related to reproduction and other areas of physiology. In relation to the reproductive role of oestrogens, they stimulate follicular growth and maturation, induce the female to begin displaying oestrous behaviour to facilitate mating, prepare the external genitalia for copulation and create favourable conditions for the development of fertilised egg cells. Oestrogens also contribute to the growth and development of mammary tissue and prepare the uterus for parturition.
Effects on reproductive organs:
Vagina: slight mucous secretion, hyperaemia, oedema
Cervix: relaxation, liquification of mucous plug (causing the bull string)
Uterus: stimulates uterine gland development, sensitization of the endometrium to oxytocin, immune activation (local), leucocyte infiltration, secretion of PGF2a and PGE2
Fallopian tube: increased motility and cilia activity
Mammary gland: stimulates mammary duct development
Corpus luteum: Luteolytic (bovine and ovine) but luteotrophic (equine and porcine)
Where oestrogens stimulate growth of follicles in the ovaries, oestrogens secreted from the ovary in the ( and ) lead to hypertrophy of the epithelium and the endometrium. Secretory glands within the uterus enlarge and secretion is initiated leading to thickening of tissues. The blood vessels supplying the uterus and external genitalia dilate and blood flow to these areas increases significantly. Oedema occurs within the uterus and surrounding connective tissues. Oestrogen also causes increased uterine muscle tone. In the cervix oestrogens stimulate increased mucus secretion and the vaginal epithelium becomes keratinised.
In males the target tissue is the brain where it causes maturation of the brain during development. This maturation process ensures the appropriate development of male sexual behaviours. E2 in the male also inhibits long bone growth.
The IARC Working Group concluded that the carcinogenic effects of estrogens and progestogens were inextricably linked to the hormonal milieu and to dose-effect relationships (IARC, 1979, 1987) The role of hormones, including progesterone, in mammary neoplasia in rodents and their relevance to human risk assessment have been reviewed (Russo & Russo, 1996), and it was noted that rodent models mimic some but not all of the complex external and endogenous factors involved in initiation, promotion, and progression of carcinogenesis.
Activin is a glycoprotein that is produced within granulosa cells in females and sertoli cells in the male. Activin is thought to play an almost directly opposite role to that of inhibin and is involved in many physiological functions including stimulation of FSH synthesis and other roles including cell proliferation, cell differentiation, apoptosis and homeostasis.
The target tissue for activin in the male is the epididymis where it enhances spermatogenesis via increased FSH secretion. Activin also enhances the effect of LH on the testes.
In the female activin has an effect on the anterior pituitary gland, specifically on gonadotroph cells, resulting in increased FSH secretion. The increased concentrations of activin results in increased FSH binding on the female follicle and FSH-induced aromatisation (increased synthesis of oestrogens). Activin also enhances the action of LH in the ovary.
A further non-reproductive role of activin is it's role in skin lesions where it is thought to stimulate keratinocytes.
To determine the role of estrogens in tubular renal damage and the subsequent reparative cell proliferation, castrated adult male Syrian hamsters were given subcutaneous pellets that released hormones at the following rates (µg/day): diethylstilbestrol, 145; estradiol, 134, estrone, 104, ethinylestradiol, 154; tamoxifen, 141; progesterone, 147; and DHT, 121.