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Endocrine Therapies
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
Unlike AR antagonists such as flutamide, by virtue of its slight intrinsic activity at the receptor, CPA is not capable of completely ablating androgenic activity in the body. Therefore, it can stimulate androgen-sensitive tumor cells in the absence of other androgens, an effect that can be blocked by co-treatment with flutamide. As a result, CPA may not be as effective in the treatment of certain androgen-sensitive conditions such as prostate cancer compared to the nonsteroidal anti-androgens such as flutamide, bicalutamide, enzalutamide, apalutamide, or darolutamide which have a direct antagonist effect at the AR. CPA also has powerful antigonadotropic effects, diminishing the GnRH-induced secretion of the gonadotropins, and thus suppressing plasma levels of Luteinizing Hormone and Follicle-Stimulating Hormone. Consequently, levels of androstenedione, testosterone, DHT, progesterone (P4) and estradiol (E2) are also reduced, while an elevation in prolactin and the sex hormone–binding globulin (SHBG) is observed. These anti-gonadotropic effects are thought to be due to over-stimulation of the PR, although CPA’s inhibition of steroidogenic enzymes may also contribute to its ability to suppress sex hormone levels.
The Pineal Gland and Melatonin
Published in George H. Gass, Harold M. Kaplan, Handbook of Endocrinology, 2020
Jerry Vriend, Nancy A.M. Alexiuk
The site(s) and mechanism(s) of action of melatonin continue to elude researchers. Using the assumption that melatonin is the active pineal hormone, we may restate the question of the site(s) of action of pineal products in terms of the site(s) of action of melatonin. It should be noted, however, that a considerable amount of research, during the 1970s and 1980s, dealt with attempts to identify, isolate, purify, and synthesize a pineal peptide hormone. Unlike the research resulting in the isolation and synthesis of hypothalamic hormones, attempts at identifying a specific pineal peptide hormone were remarkably unsuccessful. Many of these studies were attempts to isolate a specific pineal antigonadotropic hormone.161,177,445–447
Chronic pelvic pain and endometriosis
Published in Joseph S. Sanfilippo, Eduardo Lara-Torre, Veronica Gomez-Lobo, Sanfilippo's Textbook of Pediatric and Adolescent GynecologySecond Edition, 2019
Joseph S. Sanfilippo, Jessica Papillon Smith, M. Jonathon Solnik
Dienogest is an oral progestin now used as a monotherapy at a dose of 2 mg daily in patients with endometriosis. This medication is highly selective for the progesterone receptor, leading to strong progestational effects, moderate antigonadotrophic effects, and minimal androgenic, glucocorticoid, or mineralocorticoid effects.61 Multiple studies have shown dienogest to be both safe and effective in the treatment of adults with endometriosis.62–64 However, studies in the pediatric adolescent population were lacking until recently. In 2017, Ebert et al. published the results of the VISanne Study to Assess Safety in ADOlescents (VISADO study). This prospective observational study evaluated the safety and efficacy of dienogest 2 mg daily in adolescents aged 12–18 with clinically suspected or laparoscopically confirmed endometriosis. Results demonstrated that endometriosis-associated pain was substantially reduced and that the drug was very well tolerated during the 52-week trial. However, there was an associated decrease in lumbar bone mineral density with only a partial recovery after 6 months of treatment discontinuation.65 In light of these findings, it is necessary to adopt an individualized approach when prescribing dienogest, as with DMPA. One must balance the benefits of decreased pain with the potential risks to bone health in each patient, and provide counseling in this regard. Patients should also be informed that dienogest has not been tested or approved as a contraceptive, so the concomitant use of barrier contraception is necessary in sexually active teenagers.
Primary choice of estrogen and progestogen as components for HRT: a clinical pharmacological view
Published in Climacteric, 2022
However, these studies involved obtaining endometrial samples and are in our view not adequate for routine clinical use. To describe the different progestogenic endometrial potencies, transformation doses are often used, which are assessed in animal models, usually as the Clauberg/MacPhail transformation index; that is, testing the ability of the progestogen to transform the endometrium in rabbits [28–30]. To assess the antigonadotropic effects of progestogens in reproductive medicine, the ovulation inhibition dose is often assessed, usually in rats [14,28–30]. To combine these progestogenic property parameters, the uterotropic index was suggested, defined as the quotient of the transformation dose divided by the ovulation dose [29]. However, comparing those indices for the various progestogens which have been used repeatedly in the tables for years (e.g. [14,28–31]), we conclude that these indices can only reflect the experience from clinical practice to a limited extent, as the following examples may be able to illustrate, describing these properties for norethisterone (acetate) (NET, NETA) and dienogest (Table 5).
Current approaches to overcome the side effects of GnRH analogs in the treatment of patients with uterine fibroids
Published in Expert Opinion on Drug Safety, 2022
Mohamed Ali, Mohamed Raslan, Michał Ciebiera, Kornelia Zaręba, Ayman Al-Hendy
Gonadotropin-releasing hormone (GnRH) analogs have been one of the main pharmacological modalities in the treatment of UFs [8,32]. These analogs have been extensively used in clinical medicine since they were identified and synthesized in 1971 [33]. These drugs are used in gynecology and oncology for the modulation of the pulsatile release of GnRH. They bind to the receptor of the frontal lobe of the pituitary gland inhibiting the secretion of luteinizing hormone (LH) and follicle-stimulating hormone (FSH). LH and FSH are peptide hormones that regulate ovarian and testicular function and are essential for normal growth, sexual development, and reproduction. These pituitary gonadotropins are under the control of the above mentioned GnRH, which is produced in the hypothalamus and released in response to the circulating levels of estrogens and progesterone [34]. GnRH analogs are made of different peptides and are structurally related to GnRH. Very recently researchers have also obtained new small molecules (e.g. elagolix), which are structurally distinct (non-peptide) from and unrelated to GnRH analogs [35]. The majority of the above-mentioned substances present antigonadotropic properties. However, some may present pro-gonadotropic properties (e.g. gonadorelin), depending on whether they act to increase or decrease gonadotropin release [34].
Pharmacodynamics of combined estrogen-progestin oral contraceptives 3. Inhibition of ovulation
Published in Expert Review of Clinical Pharmacology, 2018
Carlo Bastianelli, Manuela Farris, Elena Rosato, Ivo Brosens, Giuseppe Benagiano
The action of this new progestin has been investigated in 13 healthy subjects to whom daily doses of 1.25, 2.5, or 5 mg were administered [44]. Nomegestrol acetate (NOMAC) inhibited ovulation in all women, with LH and P levels being constantly depressed. With 2.5 and 5 mg doses, plasma E2 remained low with high FSH values. With 1.25 mg, circulating levels of E2 were similar to those observed during the control follicular phase, with a concomitant decrease in FSH secretion. When the antigonadotropic activity of NOMAC was tested [45,46], it was found that it is not antagonized by flutamide and is not mediated via the androgen receptor. The exact mode of action of NOMAC was then investigated in 10 normally cycling women, 3 with McCune-Albright syndrome (MCA, characterized by gonadotropin-independent ovarian function), and 5 with functional hypothalamic amenorrhea. Ovulation was suppressed in all subjects when treated with 5 mg/daily NOMAC. In normal subjects, mean plasma LH levels, LH pulse frequency, and the LH response to exogenous GnRH were significantly decreased. A direct effect of NOMAC on the ovaries was ruled out, since in subjects with MCA syndrome, ovaries were unmodified. In subjects with functional hypothalamic amenorrhea, pulsatile GnRH administration recreated a normal ovulatory menstrual cycle, but administration of NOMAC prevented ovulation, as well as any increase in plasma E2, and decreased the amplitude of LH pulses. In a 6-month long trial at the daily dose of 5 mg, NOMAC significantly decreased E2 and P levels (p < 0.001) [47].