GONADAL HORMONES:ESTROGENS AND ANDROGENS

Rich Minshall, Associate Professor of Pharmacology

rminsh@uic.edu

Chapter 40. The Gonadal Hormones & Inhibitors

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Control of androgen secretion in males

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(1) competitive inhibition of GnRH receptors(2) stimulation (+, pulsatile administration) or inhibition via desensitization of GnRH receptors(–, 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

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Sertoli cells in the testis synthesize and secrete a variety of active proteins, including müllerian duct inhibitory factor, inhibin, and activin.Leydig cells, upon LH stimulation, produced testosterone in the spaces between the seminiferous tubules.

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.Activin is composed of the two  b subunits, stimulates pituitary FSH release 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

Testis

Steroid synthesis

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The biosynthetic pathwayof the androgens and estrogens

19-carbon precursors are synthesized primarily in the ovaries, testes, and adrenals

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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

AGING

Clinical Uses of Androgens

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replace or augment endogenous androgen secretion in hypogonadal men

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.

ANDROGEN REPLACEMENT

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Table 40–6 Androgen Preparations for Replacement Therapy.

Drug Route of Administration

Dosage

Methyltestosterone Oral 25–50 mg/d

Sublingual (buccal) 5–10 mg/d

Fluoxymesterone Oral 2–10 mg/dTestosterone enanthate Intramuscular See text

Testosterone cypionate Intramuscular See text

Testosterone Transdermal 2.5–10 mg/d Topical gel (1%) 5–10 g/d

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ANTIANDROGENSInhibition of Steroid Precursor Conversion to AndrogensKetoconazole-an inhibitor of adrenal and gonadal steroid synthesisAbiraterone- inhibits the 17-hydroxylation of progesterone or pregnenolone to androgensFinasteride, a steroid-like orally active inhibitor of of 5a-reductase that causes a reduction in dihydrotestosterone levels. Moderately effective in reducing prostate size in men with benign prostatic hyperplasia and is approved for this use in the USA. The dosage is 5 mg/d.Dutasteride is a similar orally active steroid derivative with a slow onset of action and a much longer half-life than finasteride. The dose is 0.5 mg daily.

Receptor InhibitorsFlutamide- potent anti-androgen that has been used in the treatment of prostatic carcinoma. Although not a steroid, it behaves like a competitive antagonist at the androgen receptor.Cyproterone and cyproterone acetate are effective antiandrogens that inhibit the action of androgens at the target organBicalutamide and nilutamide- potent orally active antiandrogens that can be administered as a single daily dose and are used in patients with metastatic carcinoma of the prostate.Spironolactone- a competitive inhibitor of aldosterone that also competes with dihydrotestosterone for the androgenreceptors in target tissues. It also reduces 17-hydroxylase activity, lowering plasma levels of testosterone and androstenedione. It is used in dosages of 50–200 mg/d in the treatment of hirsutism in women and appears to be as effective as finasteride, flutamide, orcyproterone in this condition.GOSSYPOL-abandoned as a candidate male contraceptive.

ANDROGEN SUPPRESSION

ANDROGEN SUPPRESSION

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Control of ovarian secretion and the

actions of its hormones.In the follicular phase, the ovary produces mainly estrogens; In the luteal phase, it produces estrogens and progesterone. SERMs, selective estrogen receptor modulators

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Hormonal relationships of the human menstrual

cycle

Estrogen and Progesterone

production and negative feedback

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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.

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Estrogen production from

progesterone and testosteronevia Aromatase

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Estrogen and synthetic analogs

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Progesterone and synthetic analogs

Structural Formulas of Selected Estrogens

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Physiological and Pharmacological Actions of Estrogen

Developmental Actions: Puberty and secondary sexual characteristics of females growth and development of the vagina, uterus, and fallopian tubes with other hormones cause enlargement of the breasts, promotion of

ductal growth, stromal development, and the accretion of fat; molding body contours, shaping the skeleton, and growth spurt of the long bones

growth of axillary and pubic hair and pigmentation of the genital region; regional pigmentation of the nipples and areolae that occur after the first term of pregnancy

Metabolic Effects of E: blocks bone resorption and increases bone formation increases the level of the hydroxylase that converts vitamin D to 1,25-

dihydroxyvitamin D3 in the kidney slightly elevates serum triglycerides and reduces total serum cholesterol

levels increases HDL levels and decreases LDL values alters bile composition by increasing cholesterol secretion and decreasing

bile acid secretion, leading to increased saturation of bile with cholesterol which may be the basis for increased gallstone formation

decrease slightly fasting levels of glucose and insulin, increase plasma levels of cortisol-binding globulin (CBG or transcortin),

thyroxine-binding globulin (TBG), and sex steroid-binding globulin (SSBG), which binds both androgens and estrogens 19

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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- HDL- TG- LDL- total cholesterol

Other- increases angiotensinogen and transport

proteins

Physiological Effects of Estrogen

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Physiological Effects of Estrogen

Alters vascular reactivity (endothelial mediators of contraction and relaxation)

- endothelin-1

- TXA2 receptors

- angiotensin II receptors

- superoxide free radicals

- nitric oxide synthase expression and activity

therefore nitric oxide

Estrogen Receptor Isoforms

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Estrogen Receptor Signaling

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Mechanisms of Steroid Hormone Signaling

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AP-1

Sp1

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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

Elimination of Estrogens

Therapeutic Uses of E2:

• pharmacological considerations for E use in OC and HRT are different because of the dose

• conjugated estrogens for HRT (0.625 mg/day for most women; 1.25 mg in some patients)

• combination oral contraceptives in current use employ 20 to 35 mg/day of ethinyl estradiol

• Conjugated estrogens and ethinyl estradiol differ widely in their oral potencies; for example, a dose of 0.625 mg of conjugated estrogens generally is considered equivalent to 5 to 10 mg of ethinyl estradiol

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Physiological and Pharmacological Actions of Progesterone:

Neuroendocrine Actions:• P decreases the frequency of the hypothalamic pulse generator and increases the

amplitude of LH pulsesReproductive Tract:• P released during the luteal phase of the cycle decreases estrogen-driven

endometrial proliferation and leads to the development of a secretory endometrium

• decline in P release from the corpus luteum at the end of the cycle determines onset of menstruation

• P influences the endocervical glands; the abundant watery secretion of the estrogen-stimulated structures is changed to a scant, viscis material, decreasing penetration of the cervix by sperm

• E-induced maturation of the vaginal epithelium is modified toward the condition of pregnancy by P

• P is very important for the maintenance of pregnancy: suppress menstruation and uterine contractility, which led to the use of progestins to prevent threatened abortion. However, such treatment is of questionable benefit because diminished P is rarely the cause of spontaneous abortion

Mammary Gland:• P, acting with E, induces proliferation of the acini of the mammary gland• during the normal menstrual cycle, the mitotic activity in the breast epithelium is

very low in the follicular phase and then peaks in the luteal phase… P triggers a single round of mitotic activity

• in contrast, in the endometrium, proliferation is greatest in the follicular phase due to increasing E and is opposed by P in the second half of the cycle

• hormonal control of proliferation is thus different in breast and endometrium; these cell-specific effects should be kept in mind when interpreting therapeutic and untoward effects of E and P

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Physiological and Pharmacological Actions of Progesterone:

CNS Effects:• an increase of about 1°F may be noted midway through the normal

menstrual cycle at the time of ovulation• the temperature rise persists for the remainder of the cycle until the onset

of the menstrual, and thus clearly due to P. The mechanism of this effect is unknown

• P increases the ventilatory response of the respiratory centers to carbon dioxide and leads to reduced arterial and alveolar PCO2 in the luteal phase of the menstrual cycle and during pregnancy

• P may have depressant and hypnotic actions, perhaps inducing drowsiness after administration

Metabolic Effects:• P increases basal insulin levels and the rise in insulin after carbohydrate

ingestion• long-term administration of more potent progestins, such as norgestrel,

may decrease glucose tolerance• P stimulates lipoprotein lipase activity and seems to enhance fat

deposition• P and medroxyprogesterone acetate (MPA) cause either no effect or

modest reduction in serum HDL; 19-nor progestins may cause more pronounced decrease in HDL levels, possibly due to androgenic activity. Thus, progestins may diminish the beneficial effects of estrogens on serum lipoprotein profiles in situations where the two agents are given together, such as OCs and HRT.

• P may diminish the effects of aldosterone in the renal tubule and cause a decrease in sodium reabsorption that may increase mineralocorticoid secretion from the adrenal cortex

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Progesterone Receptor• Progestins are lipophilic and diffuse freely into cells where they bind to the PR

(PR-A and PR-B)• PRs are ligand-activated nuclear transcription factors that interact with a

progesterone response element in target genes to regulate their expression• PRs are expressed in the female reproductive tract, the mammary gland, the

CNS (including the pulse generator in the hypothalamus), and the pituitary• expression of PRs is induced by estrogens; its presence is a common marker for

E action• A single PR gene yields two forms of the receptor, the so-called A and B forms

that arise from two translational start codons; the physiological and pharmacological significance of the two forms is unknown, but may relate to intracellular vs cell surface membrane PR

• progestins enhance differentiation and oppose the actions of E to stimulate cell proliferation by decreasing ER levels, increasing local metabolism of estrogens to less active metabolites, or induction of gene products that blunt cellular responses to estrogenic agents

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Progesterone derivatives

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Biological Activity of Progestins

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Relationship Between 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.

Hormone Replacement Therapyand Fertility Drugs

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Menopause: cessation of menses; loss of ovarian function leading to a state of permanent amenorrheaOvarian follicle no longer responds to gonadotropin, thus estrogen is not producedLack 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

Menstrual irregularity

Mood swings

Loss of concentration

Hot flashes

Vaginal dryness

Last period

Osteoporosis

Heart Disease

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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).

Menopause

• Vasomotor instability (hot flashes), night sweats

• Increase incidence of cardiovascular disease

• Osteoporosis• Genitourinary atrophy• Metabolic changes – fat redistribution• Skin changes• Insomnia, fatigue, dysphoria, anxiety• Loss of memory?, susceptibility to

dementia? 36

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Proposed Benefits of HRTCardiovascular• Decreased incidence of cardiovascular disease• Improved lipid profiles• Vasodilatory effects• Antiplatelet activity• Decreased fibrinogen levels• Direct myocardial effects• Antioxidant activity

• Non-Cardiovascuclar• Prevention of bone loss*• Treatment of vasomotor symptoms (hot flashes)*• Prevention of colon cancer• Prevention of Alzheimer’s disease• Prevention of urinary incontinence• Alleviation of sleep disorders

* known effects of estrogen

Routes and Compounds

• Oral Estrogens– Premarin, Cenestin– Esterified estrogen– Ethinyl estradiol– Estrone sulfate– Micronized estrogen

• Transdermal Estrogens– Less effects on liver –

no first pass effect– Patches, creams

• Vaginal Estrogens– Vaginal creams –

including premarin– Vaginal ring

• Parenteral Estrogens– Estrogen esters

• Progesterones– Medroxyprogesterone

acetate– Norethindrone – etc.– Micronized

progesterone38

Examples of HRT Preparations

• Prempro – continuous combinedPremarin and Provera

Premphase - continuous sequential Premarin 14 days then Premarin plus Provera for next 14 days

• FEMHRT – continuous combined ethinyl estradiol plus norethindrone

• Ortho-Prefest – continuous combined; 6 day cycle – day 1-3 micronized estradiol and day 4-6 micronized estradiol with norgestimate

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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.

Hospital Case-Control

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Pop Case-Control

Prospective Internal

ControlCross-Sectional

Prospective External

Control

All Studies Combined

Prospective Internal

Control andCross Sectional 0 0.5 1

RR

1.5 2

Study Type

Relative Risk for Estrogen Use and Coronary Heart Disease