The epithelial ovarian carcinomas, which make up more than 85% of human ovarian cancer, arise in the ovarian surface epithelium (OSE). The etiology and early events in the progression of these carcinomas are among the least understood of all major human malignancies because there are no appropriate animal models, and because methods to culture OSE have become available only recently. The objective of this article is to review the cellular and molecular mechanisms that underlie the control of normal and neoplastic OSE cell growth, differentiation, and expression of indicators of neoplastic progression. We begin with a brief discussion of the development of OSE, from embryonic to the adult. The pathological and genetic changes of OSE during neoplastic progression are next summarized. The histological characteristics of OSE cells in culture are also described. Finally, the potential involvement of hormones, growth factors, and cytokines is discussed in terms of their contribution to our understanding of the physiology of normal OSE and ovarian cancer development.

/pdf/ovarian-surface-epithelium-biology-endocrinology-and-1ln38b94gz.pdf

Ovarian surface epithelium: biology, endocrinology, and pathology.

It is with deep gratitude that I receive the honour of having been selected by the Trustees of the Gaddum Memorial Fund to deliver the Sixth Gaddum Memorial Lecture. Among many other topics, Sir John Gaddum was interested in neurotransmission and he made important contributions in the field of cholinergic (Chang & Gaddum, 1933; Feldberg & Gaddum, 1934) and noradrenergic transmission (Gaddum & Kwiatowski, 1939; Gaddum, Peart & Vogt, 1949; Gaddum, 1950). The work of Sir John Gaddum is also linked to the discovery of other putative neurotransmitters like Substance P and 5hydroxytryptamine (von Euler & Gaddum, 1931; Gaddum, 1953; Amin, Crawford & Gaddum, 1954). Although I never had a chance to meet Sir John Gaddum personally, as a pharmacologist I always admired his work and his important contributions. In addition, I had the privilege of working for two years with one of Gaddum's collaborators, Dr Marthe Vogt. The time spent with Dr Marthe Vogt in Babraham (1967 and 1968) was a stimulating and rewarding experience. It was during these two years that my interest in noradrenaline release during nerve stimulation started and this has developed further during the last eight years. The topic of the lecture will be the presence of presynaptic receptors in noradrenergic nerve endings and their role in the regulation of the release of the neurotransmitter upon arrival of nerve impulses.

https://bpspubs.onlinelibrary.wiley.com/doi/pdf/10.1111/j.1476-5381.1977.tb07526.x

Sixth gaddum memorial lecture national institute for medical research, mill hill, january 1977

This review comprises the pharmacokinetics and pharmacodynamics of natural and synthetic estrogens and progestogens used in contraception and therapy, with special consideration of hormone replacement therapy. The paper describes the mechanisms of action, the relation between structure and hormonal activity, differences in hormonal pattern and potency, peculiarities in the properties of certain steroids, tissue-specific effects, and the metabolism of the available estrogens and progestogens. The influence of the route of administration on pharmacokinetics, hormonal activity and metabolism is presented, and the effects of oral and transdermal treatment with estrogens on tissues, clinical and serum parameters are compared. The effects of oral, transdermal (patch and gel), intranasal, sublingual, buccal, vaginal, subcutaneous and intramuscular administration of estrogens, as well as of oral, vaginal, transdermal, intranasal, buccal, intramuscular and intrauterine application of progestogens are discussed. The various types of progestogens, their receptor interaction, hormonal pattern and the hormonal activity of certain metabolites are described in detail. The structural formulae, serum concentrations, binding affinities to steroid receptors and serum binding globulins, and the relative potencies of the available estrogens and progestins are presented. Differences in the tissue-specific effects of the various compounds and regimens and their potential implications with the risks and benefits of hormone replacement therapy are discussed.

https://www.hormonebalance.org/images/documents/Kuhl%2005%20%20Pharm%20Estro%20Progest%20Climacteric.pdf

Pharmacology of estrogens and progestogens: influence of different routes of administration.

CORTICOSTERONE is one of the principal steroids secreted by the rat adrenal gland1–3 and it is well established that various noxious psychological and physiological stimuli promote the release of this substance into the blood. Because we are interested in the action of such corti-costeroids on biochemical processes in the brain, we attempted to determine the degree to which circulating, radioactive corticosterone enters and remains in the brain. Furthermore, because the limbic system of the brain is implicated in the control of the secretion of ACTH4–6 and in the affective behavioural responses7–9, we were particularly interested to see whether structures in the limbic system retain corticosterone in a higher concentration than other areas of the brain. Published work on the uptake of the oestradiol by the brain10–13 indicates that the hypothalamus retains that hormone.

Selective Retention of Corticosterone by Limbic Structures in Rat Brain

OESTROGENS are more readily accumulated and retained in responsive cells than in cells that are not their targets1. Cytoplasmic macromolecules2 which specifically interact with oestradiol and other steroid hormones seem to mediate transfer of the agonist to the nuclear chromatin, where the complex is believed to promote expression of the phenotypic effects3–6. It is generally assumed that the hormone diffuses passively to “cytoplasmic” receptors which determine the cellular specificity of response7. But some experiments indicate that steroid hormones interact with components of biological membranes and may enter their respective target cells by a membrane-mediated process8–12 which is saturable and temperature-dependent13–17. We have investigated steroid-binding components associated with the plasma membranes of cells isolated from endometrium, liver and intestinal mucosa. Endometrial and liver cells show substantial binding to oestrogen immobilised by covalent linkage to an inert support, while intestinal cells have no such binding sites. The relative quantity of these steroid receptors at the outer surfaces of cells from diverse tissues corresponds well with the capacity of a given cell to accumulate and retain oestrogen.

Specific binding sites for oestrogen at the outer surfaces of isolated endometrial cells

The accumulation of H 3 -norepinephrine and its metabolites has been measured in cocaine-treated, isolated, perfused rat hearts. This accumulation appears to occur outside of sympathetic neurons. Adrenergic blocking agents reduce this extraneuronal concentration of H 3 -norepinephrine and the metabolites. The alpha -adrenergic blocking agents are more potent than the beta -adrenergic blocking agents. The decreased concentrations of the metabolites in the presence of the adrenergic blocking agents do not appear to be related to inhibition of catechol-O-methyl transferase or monoamine oxidase but rather to the reduced concentrations of norepinephrine. It is proposed that the adrenergic blocking agents may inhibit an extraneuronal transport mechanism, thereby reducing the access of norepmnephrine to the intracellular metabolizing enzymes.

Inhibition of the extraneuronal accumulation and metabolism of norepinephrine by adrenergic blocking agents.

Circulating estradiol is selectively accumulated by the anterior pituitary, uterus, vagina, hypothalamus, septum and preoptic region. Pretreatment with the progestin norethynodrel reduced the H 3 -estradiol concentrations in the anterior pituitary, uterus, vagina, heart, adrenal, hypothalamus, preoptic region and septum. Treatment with norethynodrel after H 3 -estradiol administration reduced the radioactive concentration only in the uterus and vagina. Norethynodrel appeared to function as a competitive inhibitor of estradiol for binding. Evidence has been presented for an estradiol saturable binding mechanism in the anterior pituitary, uterus, vagina, and hypothalamus.

Selectivity of estrogen distribution in tissues

The in vitro interaction of 3H-estradiol with macromolecules from various organs was studied. Tissues from ovariectomized rats were homogenized in Tris-HCl containing EDTA and radioactive estradiol mixed with the 100,000 × g supernatants. After incubation macromolecular bound radioactivity was separated by gel filtration. Higher concentrations of radioactive estradiol were found in the macromolecular fractions from the hypothalamus, anterior pituitary and uterus than from the cerebrum, cerebellum, heart or plasma. The binding molecules from the hypothalamus, anterior pituitary and uterus were found to have the following properties. Nonradioactive estradiol (10−7m) reduced binding, whereas progesterone or testosterone (10−5m) did not. Intravenous injection of nonradioactive estradiol decreased subsequent binding of 3H-estradiol in vitro. The binding molecules contain protein and appear to have sulfhydryl groups that influence the interaction with estradiol. (Endocrinology 86: 1313, 1970)

3H-Estradiol: In Vitro Binding to Macromolecules from the Rat Hypothalamus, Anterior Pituitary and Uterus

The effect of immediate pretreatment with cyproterone, progesterone and unlabeled testosterone on the distribution and metabolism of 3H-testosterone in mature, castrated male rats was investigated. One hr after its intravenous administration, 3H-testosterone was rapidly metabolized such that only 30% of the radioactivity in plasma remained as testosterone, the major portion consisting of polar metabolites. The concentrations of 3H-testosterone in seminal vesicle and pituitary were 10 and 3 times greater than plasma, respectively. Even larger amounts of 3H-dihydrotestosterone (DHT) accumulated in these tissues, the respective concentrations being 200 and 30 times greater than plasma. Testosterone and DHT concentrations in seminal vesicle and pituitary were markedly inhibited by pretreatment with cold steroids. Progesterone, but not cyproterone or unlabeled testosterone, reduced the ratio of DHT to testosterone in the seminal vesicle. Hypothalamic and cerebral concentrations of 3H-testosterone were similar ...

Distribution and Metabolism of 3H-testosterone in Castrated Male Rats; Effects of Cyproterone, Progesterone and Unlabeled Testosterone

Cyproterone reduces the accumulation of testosterone and dihydrotestosterone in seminal vesicles 30 minutes after intravenous administration of tritiated testosterone to castrated rats. Testosterone, added in vitro, binds to macromolecules from the supernatant fraction of the seminal vesicle homogenates; this interaction is antagonized competitively by cyproterone. Cyproterone may diminish androgenic effects by competition for binding molecules.

Androgen Accumulation and Binding to Macromolecules in Seminal Vesicles: Inhibition by Cyproterone

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