GONADAL HORMONES: ESTROGENS AND ANDROGENS. Rich Minshall, Associate Professor of Pharmacology firstname.lastname@example.org Chapter 40. The Gonadal Hormones & Inhibitors. Control of androgen secretion in males. ( 1 ) competitive inhibition of GnRH receptors
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GONADAL HORMONES:ESTROGENS AND ANDROGENS
Rich Minshall, Associate Professor of Pharmacology
Chapter 40. The Gonadal Hormones & Inhibitors
(1) competitive inhibition of GnRH receptors
(2) stimulation (+, pulsatile administration) or inhibition via desensitization of GnRHreceptors
(–, continuous administration)
Lupron: synthetic analog to GnRH,
(3) decreased synthesis of testosterone in the testis
(4) decreased synthesis of dihydrotestosterone by inhibition of 5a-reductase
(5) competition for binding to cytosol androgen receptors
Sertoli cells in the testis synthesize and secrete a variety of active proteins, including müllerian duct inhibitory factor, inhibin, and activin.
As in the ovary, inhibin and activin appear to be the product of three genes that produce a common a subunit and two b subunits, A and B.
Inhibins (A and B), which contain the a subunit and one of the b subunits,in conjunction with testosterone and dihydrotestosterone ,are responsible for the feedback inhibition of pituitary FSH secretion
The biosynthetic pathwayof the androgens and estrogens19-carbon precursors are synthesized primarily in the ovaries, testes, and adrenals
Clinical Uses of Androgens
ANDROGEN REPLACEMENT THERAPY IN MEN
Androgen production falls with age in men and may contribute to the decline in muscle mass, strength, and libido.
USE AS PROTEIN ANABOLIC AGENTS
USE AS GROWTH STIMULATORS
ANABOLIC STEROID AND ANDROGEN ABUSE IN SPORTS
replace or augment endogenous androgen secretion in hypogonadalmen
used rather than gonadotropin except when normal spermatogenesis is desired
for hypopituitarism, androgens are not added to the treatment regimen until puberty, started with long-acting agents such as testosterone enanthate or cypionate in doses of 50 mg intramuscularly, initially every 4, then every 3, and finally every 2 weeks, with each change taking place at 3-month intervals. The dose is then doubled to 100 mg every 2 weeks until maturation is complete. Finally, it is changed to the adult replacement dose of 200 mg at 2-week intervals.
In the follicular phase, the ovary produces mainly estrogens;
In the lutealphase, it produces estrogens and progesterone.
SERMs, selective estrogen receptor modulators
Estrogen and Progesterone production and negative feedback
Consider the normal menstrual cycle:
1) Estrogen released from the ovary - increases the expression of estrogen receptors.
2) Estrogen increases the expression of progesterone receptors.
3) Progesterone down regulates the expression of estrogen receptors.
4) With the progesterone-elicited decrease in estrogen receptor numbers - there will be a decrease in the ability of estrogen to stimulate the production of progesterone receptors - in this way - progesterone turns itself off.
Estrogen production from progesterone and testosterone
Estrogen and synthetic analogs
Progesterone and synthetic analogs
Metabolic Effects of E:
Alters liver metabolism
Affects on clotting and fibrinolysis
- fibrinogen levels
- synthesis of clotting factors (VII, IX, X, XIII)
- plasminogen levels
- plasminogen activator inhibitor
Alters metabolism of lipoproteins
- total cholesterol
- increases angiotensinogen and transport proteins
Physiological Effects of Estrogen
Physiological Effects of Estrogen
Alters vascular reactivity (endothelial mediators of contraction and relaxation)
- TXA2 receptors
- angiotensin II receptors
- superoxide free radicals
- nitric oxide synthase expression and activity
therefore nitric oxide
Estrogen Receptor Signaling
Mechanisms of Steroid Hormone Signaling
Elimination of Estrogens
17-estradiol is primarily converted by 17b-hydroxysteroid dehydrogenase to estrone, and converted by 16a-hydroxylation and 17-keto reduction to estriol, which is the major urinary metabolite; sulfate and glucuronide conjugates also are excreted in the urine. Estrone also is converted to the catechol estrogen, or 2-hydroxyestrone which is methylated to 2-methoxyestrone
(PR-A and PR-B)
Biological Activity of Progestins
Estrogen and Progesterone
1) Estrogen exerts positive feedback on its own activity.
Estrogen stimulates the expression of estrogen receptors.
2) Estrogen must precede progesterone to elicit full progesterone sensitivity.
Estrogen stimulates the expression of progesterone receptors.
3) Progesterone has anti-estrogenic activity - which helps to terminate estrogenic activity.
- Progesterone suppresses expression of estrogen receptors.
- Progesterone facilitates the metabolism of estradiol to weaker metabolites.
- Progesterone may act as a partial agonist at the estrogen receptor.
Menopause: cessation of menses; loss of ovarian function leading to a state of permanent amenorrhea
Ovarian follicle no longer responds to gonadotropin, thus estrogen is not produced
Lack of negative feedback results in increased levels of gonadotropins (FSH and LH)
Amenorrhea lasting 1 year – average age 51.4 years
(2 yrs earlier in smokers)
Climacteric: series of physiologic, endocrinologic and psychologic changes that signify the transition from reproductive to non-reproductive life that spans several years – perimenopausal
Menopause TimetableWomen may enter menopause earlier than they realize. Estrogen levels usually drop before menopausal symptoms are seen. Below, the typical ages for various symptoms.
SYMPTOM AGE -35 40 45 50 55 60 65 70
Dropping estrogen levels
Loss of concentration
Sources: “Perimenopause: Preparing for the Change” by Nancy Lee Teaff and Kim Wright (Prima Publishing, 1996);
“Perimenopause: Changes in Women’s Health After 35” by Drs. James E. Huston and L. Darlene Lanka
(New Harbinger, 1997).
Proposed Benefits of HRT
* known effects of estrogen
Premarin and Provera
Premphase - continuous sequential Premarin 14 days then Premarin plus Provera for next 14 days
Relative Risk for Estrogen Use and Coronary Heart Disease
Reproduced with Permission. Stampfer, M. & Colditz, G. Estrogen replacement therapy and coronary heart disease: A quantitative assessment of the epidemiologic evidence. Preventive Medicine. 1991;20, 47-63.
All Studies Combined