Medical Pharmacology Chapter 31:  Endocrine: Gonadal Hormones

• Steroid Hormone Classification

  (partial listing)

  • Estrogens

    • Estradiol

    • Estrone

    • Estriol

    • Diethylstilbestrol

    • Quinestrol

    • Chlorotrianisene

    • Ethinyl estradiol (Estinyl)

    • Mestranol

  • Antiestrogens

    • Clomiphene (Clomid)

    • Tamoxifen (Nolvadex)

  • Progestins

    • Medroxyprogesterone

    • Norethindrone (Aygestin)

    • Hydroxyprogesterone

    • Norgestrel (Ovrette)

  • Anti-progestins

    • Mifepristone

  • Androgen

    • Testosterone cypionate

    • Fluoxymesterone

    • Danazol (Donocrine)

    • Testolactone

  • Anti-androgen

    • Cyproterone acetate

    • Flutamide

Some structures of Interest

• Mifepristone [anti-progestin]

•  

  Testosterone cypionate [androgen]

• Puberty: Mechanism and ovarian function 

  • Onset Neuronal Mechanism: rationale

    • Immature gonad already can be stimulated by gonadotropins (already in hypothalamus)

    • Pituitary: already responsive to hypothalamic gonadotropin-releasing hormones

    • Consequently: amygdala maturation may result in:

      1. Removal of hypothalamic median eminence cellular inhibition

      2. Thereby permitting pulsed (with appropriate frequency and amplitude) gonadotropin-releasing hormone (GnRH) release

      3. And resulting in stimulation of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) release.

    •  FSH and LH release (initially small amounts) inducing estrogen secretion (small amounts) cause:

      1. Breast development

      2. Changes in adipose tissue distribution (fat distribution)

      3. Growth spurt (ending in epiphyseal closure - long bones)

  • One Year Later

    • Increased estrogen levels induce:

      • Endometrial change

      • Periodic bleeding

    • Within a few cycles (perhaps anovulatory): normal cyclic function occurs

  • The Cycle

    • Vesicular follicles (each containing an ovum) enlarge, responding to FSH

    • 5-6 days later: one follicle begins to mature more rapidly

      1.  This follicle's granulosa cells multiply

         • Estrogen synthesis (LHinfluence) and release rate increases ­

         • Estrogen reduces ¯ FSH release

         • Estrogen causes  regression of smaller, less mature follicles

      2.  Ovarian Follicle -- Composition

         • Ovum + fluid-filled antrum lined by theca and granulosa cells

         • Peak estrogen secretion: just before midcycle

           • Granulosa cells  initiate progesterone secretion

           • These effects induce:

             • The brief surge in LH/FSH release leading yo ovulation

      3.  Follicle ruptures:

         • Ovum released into abdominal cavity;near uterine tube

         • Cavity of ruptured follicle:

           1. Fills with blood (corpus hemorrhagicum)

           2. Luteinized theca and granulosa cells proliferate

           3. These cells replace blood and form the corpus luteum

         •  Corpus luteum cells produce (for the remainder of the cycle or longer pregnancy obtains):

           • Estrogens

           • Progesterone

    • If pregnancy does not occur:

      • Corpus luteum degeneration (hormone production stops):   corpus albicans

      • Endometrium (which proliferated during follicular phase) is shed during menstruation

• Menopause:

  • Cause

    • Ovarian follicle exhaustion

    • Few, nonfunctional ova remain; supply exhausted because of:

      • Ovulation during reproductive life

      • Atresia (majority)

  • Endocrine consequences:

    • Reduced estradiol/other hormone production

    • Consequent negative feedback loss on hypothalamic-pituitary centers

    • Consequent increase in plasma gonadotropins (FSH first and achieving high levels than LH which increases later)

  • Postmenopausal ovaries: small; residual cells: stromal

  • Cyclic uterine bleeding stops

  • Ending of ovarian gametogenic/endocrine secretory function

  • Mean age: 52 years (U.S.)

  • Estrogen levels may persist due to:

    • Adrenal/ovarian steroid conversion. Examples:

      • Androstenedione leading to estrone and estradiol (in adipose, perhaps other nonendocrine tissues)

  • Preceding menopause:

    • Longer intervals between menses

    • Increased plasma FSH and LH levels

    • Ovary: less responsive to gonadotropins

• Anomalies in Ovarian Function:

  • Cyclic function disturbances: -- Possible causes

    • Some anomalies (minority) due to:

      •  Inflammatory/neoplasms destroy: ovaries, uterus or pituitary

    •  Minor disturbances (amenorrhea/anovulatory periods) -- self-limiting. Maybe associated with: emotional or environmental changes

      • Disorders induce alterations in control of hypothalamic releasing factor secretion

      • Anovulatory disturbance associated with:

        •  Excessive dieting

        •  Extreme exercise-- e.g. distance running

    •  Common causes of chronic ovulatory anomalies

      • Pituitary prolactinomas

      • 

      • Tumor/syndromes can cause excessive ovarian/adrenal androgen production

        • Androgens (e.g.,from adrenocortical sources) may modify normal ovarian function

        • Ovarian tumors may be androgen-producing:

          • Arrhenoblastomas

          • Leydig cell tumors

          • Estrogen-producing granulosa cell tumors

• Estrogenic activity

  • Many substances

    • Steroidal estrogens -- animal sources

    • Nonsteroidal estrogens -- synthetic

    • Phenols -- estrogenic

  • Natural Estrogens:

    • Major estrogens:

      • Estradiol (estradiol-17 ß, E₂)

      • Estrone (E₁)

        • Hepatically formed from estradiol

        • Formed in peripheral tissues from androstenedione/other androgens

        • Small amount: ovarian

      • Estriol (E₃)

        • Hepatically formed from estradiol

        • Rormed in peripheral tissues from androstenedione/other androgens

    • Anatomical sites of estrogen synthesis

      • Initial part eventual cycle: -- theca cells (ovarian follicle)

      • Following ovulation: --estrogens + progesterone: granulosa cells of the corpus luteum

      • During pregnancy:

        • Significant estrogens synthesis: fetoplacental unit

          • Estriol:   maternal circulation; urinary excretion

          • Maternal urinary estriol excretion: helpful for fetal condition assessment

    • Significant source of natural estrogen

      •  Stallion

      •  Equine estrogens -- recovered from urine; may be used for medical applications

        • Equilenin

    • Synthetic Estrogens

      • Chemical modifications of natural estrogens -- Major consequences = enhanced oral effectiveness

      • Examples of nonsteroidal agents with estrogenic activity:

        • Dienestrol

        • Diethylstilbestrol

        • Benzestrol

        • Hexestrol

        • Methestrol

        • Methallenestril

        • Chlorotrianisene

• Pharmacokinetics: Estrogens Following release into circulation:

  • Estradiol binds with high affinity to an a₂-globulin (sex hormone-binding globulin, (SHBG))

    • Estradiol binds to albumin with lower affinity

    • Only free estradiol is physiologically active

  • Conversion Steps

    • Estradiol converted to (by the liver/other tissues):

      •   Estrone, estriol (low estrogen receptor affinity)

      •   2-hydroxylated derivatives; conjugated metabolites --lipid insoluble leads to biliary excretion then conjugates are hydrolyzed in intestine to active, reabsorbable forms

  •  Catechol estrogens: neurotransmitters

    • Converted to 2-and 4-methoxy derivatives by catechol-O-methyltransferase

  • Estrogens: secreted (small amounts) in breast milk

  • High biliary excretion and intestinal reabsorption (enterohepatic circulation) leads to significant hepatic:peripheral effect ratio

    •  Significance: hepatic concentration may lead to undesirable results:

      • Increased clotting factor synthesis

      • Increased plasma renin substrate

    •  To minimize enterohepatic effects-- estrogens for peripheral actions (postmenopausal women)-- use routes of administration that avoid first pass effects (vaginal, transdermal, injection)

•  Mechanism:  Sequence

  1. Sex hormone-binding globulin binds plasma estrogens (plasma) forming a complex.

  2. Complex dissociation followed by cell entry leading to intracellular estrogen receptor binding

     •   Estrogen Receptors

       • Steroid/thyroid receptor superfamily

       • Location: mainly nuclear -- associated with stabilizing proteins

       • Hormone + receptor interaction causes a conformational change with release of associated, stabilizing proteins (primarily hsp90)

     •  Estrogen -- estrogen receptor complex

       • Forms homodimers

       • Homodimers buying to estrogen response elements (EREs) regulating transcription various genes

       • ERE -- receptor dimer interaction involves transcription element proteins

       • Receptor complex: does not bind exclusively to gene promoter regions

     •  Hormone action and cellular specificity

       • Depends on variety/number of receptors sites and transcription factors

     • Genomic Effects: estrogen

       • Consequence of proteins synthesized in response to gene(s) activation

       • Also indirect genomic effects:

         •   Paracrine effects of cytokines produced by regional cells under regulation by target cell proteins, induced by estrogen

  • Membrane Estrogen Receptors

    • Consequences of estrogen-activation of membrane receptors (no gene activation) include, e.g.:

      • Rapid, granulosa cell calcium uptake

      • Increased uterine blood flow

• Female  Maturation:  estrogen required for normal female maturation

  • Stimulate the development of:

    •  Vagina

    •  Uterus

    •  Uterine tubes

    •  Secondary sex characteristics

  • Stimulation by estrogen

    •  Stromal development

    •  Ductal growth in the breast

    •  Growth spurt/closing of the epiphyses of long bones (puberty)

    •  Axillary and pubic hair; promote redistribution of body fat, resulting in typical female body contours

    •  Skin pigmentation -- particularly in the nipple region, areolae, and genital areas

• Endometrial Effects of estrogen

  •  Promotes endometrial lining development

  •  Continuous, excessive estrogen exposure may lead to endometrial hyperplasia (may cause abnormal bleeding)

  •  Estrogen and progesterone coordination during normal menstrual cycle:

    • Periodic bleeding

    • Endometrial lining shedding

• Metabolic Effects of estrogen

  1. Maintenance of normal skin/blood vessel structure (in women)

  2. Decrease rate of bone resorption (parathyroid hormone antagonism)

  3. Promote intestinal absorption (decrease bowel motility)

  4. Hepatic effects are metabolic and result in increased circulating concentrations of:

     • Transcortin (CBG)

     • Thyroxine-binding globulin (TBG)

     • Sex hormone-binding globulin (SHBG)

     • Renin substrate

     • Transferrin

     • Fibrinogen

     • These effects tend to increase the circulating concentrations of thyroxine,estrogen, testosterone, iron, copper, other compounds

  5. Plasma Lipid Effects:

     • Increased in high-density lipoproteins

     • Slight decrease in low-density lipoproteins

     • Decreased cholesterol

     • Increase plasma triglycerides

       • Increased triglycerides synthesis

       • Decreased lipid oxidation ketones

• Blood Coagulation Effects of Estrogen

  • Estrogen: causes enhancement of blood coagulation

    • Increased circulating factors II, VII, IX, X. (note hepatic effects)

    • Decreased antithrombin III

    • Increased plasminogen concentration

    • Decreased platelet adhesiveness

• Miscellaneous Effects: Estrogen

  1. Induce progesterone receptor synthesis

  2. Sffect human libido

  3. Promote renal Na/water retention

  4. Influence sympathetic nervous system-mediated smooth muscle tone

• Primary Hypogonadism

  • Estrogens for estrogen replacement therapy

  • Estrogen deficiency due to:

    1. Castration

    2. Primary failure of ovarian development

    3. Menopause

  • Treatment of primary hypogonadism

    •  Initiation time -- 11-13 years of age

      • Rationale:

        1. Stimulation of secondary sex characteristics, menses

        2. Stimulation of growth

        3. Avoiding psychological effects of the delayed puberty

    •  Agents used:

      • Conjugated estrogens

      • Ethinyl estradiol

  • Following growth completion transition to chronic therapy (estrogen + progestins)

•  Postmenopausal Hormonal Treatment: estrogens

  •  This usage is likely associated with significant health risks with overall risks of estrogen plus progestin outweighing benefits.

    • RISKS included increased likelihood of breast cancer, heart disease, stroke and blood clots. As a result, in general postmenopausal hormonal treatment, if needed, should be very limited in duration.

  •  Longer-lasting changes associated with menopause: those that may influence health/well-being of postmenopausal women:

    •   Accelerated bone loss, predisposing to:

      • Wrist fractures

      • Vertebral fractures

      • Hip fractures

    • Osteoporosis:

      • Close correlation between estrogen loss and osteoporosis development has been identified.

      • Frequency of vertebral/hip fractures between ages of 60 -90 years of age: women -- 25%; men-- 10%

      • Highest hip fracture frequency: elderly, white women

      • Major cause of morbidity/death; death frequency -- 30% or more in patients over eighty years of age.

      • Other factors influencing osteoporosis development:

        • Smoking, diet, physical activity, general health, estrogen deprivation

    • Lipid changes: increasing risk of cardiovascular disease

  • Bone:  estrogen replacement effective

    • Factors influencing osteoporosis development:

      • Amount of initial bone present

      • Calcium intake

      • Physical activity

      • Risk is highest in:

        • Thin, caucasian, inactive women with low calcium intake + strong family history

    • Estrogen replacement

      • Conjugated Estrogen or ethinyl estradiol effective

        • In preventing decrease in bone density recurring menopause

        • Insuring adequate daily calcium intake is also important

  • Cardiovascular Issues

    •  Following oophorectomy or menopause, estrogen levels fall:

      • Increase in plasma cholesterol + LDL

      • Decrease in LDL receptors

      • +/-HDL

    • Following estrogen replacement:

      •  Decrease in total cholesterol

      •  Decrease in LDL cholesterol

      •  Increase in HDL cholesterol

      •  50% reduction in myocardial infarction frequency

      •  As much as 40% reduction in fatal stroke frequency

  • Management of hot flushes

    • symptomatic relief -- use lowest estrogen does possible

      • Limited period of treatment to reduce breast cancer risk

    • Following hysterectomy: estrogens alone (frequency-five days per week or continuously; progestins are not required to reduce endometrial hyperplasia or cancer risk)

    • Symptoms relieved by estrogen replacement:

      • Hot flushes

      • Sweating

      • Insomnia

      • Atrophic vaginitis

    •  Symptoms which may not be relieved by estrogen replacement:

      • Psychopathological conditions, including depression

  •  Atrophic vaginitis

    •  Post-menopausal symptoms limited to atrophic vaginitis and limited osteoporosis risk:

      •  Topical treatment:

        • Locally administered estrogens not subject to first-pass effect (negative hepatic consequences minimized)

  • Cancer

    •  Estrogen monotherapy: increased risk of endometrial carcinoma

    •  Progestational agent + estrogen: prevents endometrial hyperplasia; markedly reduced cancer risk

      • Combinations: estrogen + progestin medroxyprogesterone: reduced risk (protocol: -- estrogen, first 25 days of the month; progestin medroxyprogesterone added during last 10-14 days of month)

        •  Cyclic bleeding may occur

        •  Cyclic bleeding eliminated with treatment combining conjugated equine estrogens + medroxyprogesterone:

          • This combination will also:

            • Control vasomotor symptoms

            • Prevent genital atrophy

            • Maintained bone density

            • Promote favorable lipid profiles

          • Associated with endometrial atrophy

            • Some breakthrough bleeding

            • Continues therapy: disadvantage -- periodic biopsy if bleeding occurs after first few months

  • Therapeutic approach if estrogen replacement therapy is contraindicated

    • Progestational drugs

    • Clonidine

  • Other Uses

    • Estrogen + progestins:

      • Ovulation suppression for treating intractable dysmenorrhea

      • Ovarian suppression used to manage hirsuitism and amenorrhea due to excessive ovarian androgen secretion

    • Estrogen:

      • Stop excessive uterine bleeding -- caused by endometrial hyperplasia

      • May stop blood loss (temporarily)

•   Adverse Effects: estrogen

  • Use smallest dose possible and shortest treatment duration to minimize adverse effects

  • Estrogen therapy:  major cause of postmenopausal bleeding

    • Other cause: endometrial carcinoma

    • Endometrial hyperplasia: prevented by a progestational agent along with estrogen in each cycle

  • Nausea:  common (minimized by smallest effective estrogen dose)

  • Breast tenderness is common (minimized by smallest effective estrogen dose)

  • Hyperpigmentation

  • Increased frequency of:

    • Gallbladder disease

    • Hypertension

    • Cholestasis

    • Migraine headaches

  •  Cancer:  estrogens

    • Chronic estrogen use:

      •  Increase in breast cancer risk

      •  Following unilateral breast cancer surgery:

        •  Tamoxifen treatment reduces by 35% breast cancer risk on contralateral side

        •  Tamoxifen is usually well tolerated.

          • Positive, estrogen-like changes in plasma lipids

          • Stabilizes bone loss

      • Increase risk of endometrial cancer with estrogen monotherapy

        • Could be dependent on estrogen dosage and duration-more research is probably needed here

        • Cancer and Estrogen-Replacement Administration [Author: Colditz GA, Title: Relationship between estrogen levels, use of hormone replacement therapy, and breast cancer.;Source: J Natl Cancer Inst; 90(11):814-23 1998   UI: 98286833

        • "We sought to determine the strength of the evidence suggesting that estrogen and postmenopausal replacement hormones play a role in the development of breast cancer.

          • We reviewed the existing English language literature in MEDLINE on hormones and breast cancer, including reports on cell proliferation and endogenous hormone levels, as well as epidemiologic studies of the relationship between the use of postmenopausal hormones and the risk of breast cancer in women.

          • A factor that increases the probability that cancer will develop in an individual has been defined as a cancer cause.

            • The Hill criteria for demonstrating a link between environmental factors and disease were used to review the evidence for a causal relationship between female hormones and breast cancer.

          • We found evidence of a causal relationship between these hormones and breast cancer, based on the following criteria: consistency, dose-response pattern, biologic plausibility, temporality, strength of association, and coherence.

          • The magnitude of the increase in breast cancer risk per year of hormone use is comparable to that associated with delaying menopause by a year.

          • The positive relationship between endogenous hormone levels in postmenopausal women and risk of breast cancer supports a biologic mechanism for the relationship between use of hormones and increased risk of this disease.

          • The finding that the increase in risk of breast cancer associated with increasing duration of hormone use does not vary substantially across studies offers further evidence for a causal relationship.

          • We conclude that existing evidence supports a causal relationship between use of estrogens and progestins, levels of endogenous estrogens, and breast cancer incidence in postmenopausal women.

          • Hormones may act to promote the late stages of carcinogenesis among postmenopausal women and to facilitate the proliferation of malignant cells.

          • Strategies that do not cause breast cancer are urgently needed for the relief of menopausal symptoms and the long-term prevention of osteoporosis and heart disease. (99 Refs)"

      • Decreased risk of endometrial cancer with estrogen combined with progestin.

    • Diethylstilbestrol:

      • Vaginal carcinoma in young women whose mothers received diethylstilbestrol early pregnancy

      • Low incidence (1 per 1000) has been considered to low to establish cause-and-effect relationship with complete certitude:

        • In the same population, increased risk for:

          •  Infertility

          •  Premature delivery

          •  Ectopic pregnancy

      • No role of diethylstilbestrol during pregnancy

        • May be used in management of prostatic cancer

        • Alternative use: "morning-after" contraceptive

•  Contraindications:  estrogen in patients:

  • With estrogen-dependent neoplasm (e.g. endometrial carcinoma)

  • At higher risk for or with breast carcinoma

  • With undiagnosed genital bleeding

  • With liver disease

  • Oredisposed to thromboembolic disease

• Natural progestins: Progesterone

  • Progesterone: Most important human progestin

    • Precursor to:

      • Estrogens

      • Androgens

      • Adrenocortical steroids

  • Synthetic sites:progesterone

    • Ovary

      • By the corpus luteum

    • Testis

    • Adrenal from circulating cholesterol

    • Placenta (during pregnancy)

• Synthetic Progestins I

  • Variable Properties within the group:

  • Most closely related: 21-carbon agents, e.g.

    • Hydroxyprogesterone

    • Hydroxyprogesterone

    • Megestrol

    • Dimethisterone

  • Newer, "third-generation" synthetic progesterones

    • Components of oral contraceptives

    • Includes newer "19-nor, 13-ethyl" steroids, e.g.

      • Gestodene

      • Norgestimate

      • Desogestrel

• Pharmacokinetics: progesterone

  • Progesterone

    • Rapidly absorbed

    • Half-life = approximately five minutes

    • Extensive first pass metabolism (oral administration -- ineffective)

    •  Hepatic Metabolism:progesterone

      • Metabolized to pregnanediol

      • Urinary excretion product: pregnanediol glucuronide

        • Pregnanediol glucuronide levels: useful to assess progesterone secretion

        • Other metabolites formed in small quantities

• Physiological mechanisms: progesterone

  • Mechanism:  progesterone

    1. Progestins enter the cell

    2. Binds to progesterone receptors (distributed between nucleus and cytoplasm)

    3. Ligand-receptor complex: binds to nuclear response elements, activating gene transcription

       • Response elements: similar to corticoid response elements

       • Response specificity dependencies:

         •  Receptor type present

         •  Cell-specific transcription factors

    4. Progesterone-receptor complex dimerizes then binds to DNA

• Some Other Progesterone Effects

  • Competes with aldosterone and renal tubule: decreasing sodium reabsorption

  • Reduce other reabsorption promotes increased adrenocortical aldosterone secretion

  • Increases body temperature

  • Increases developed for response to CO₂

    • Reduces arterial/alveolar PCO₂ during pregnancy

    • Reduces PCO₂ during menstrual cycle luteal phase

  • Depressant/hypnotic CNS effects

  • Causes alveolobular development of the breast secretory apparatus

  • Following ovulation

  • Decreases amino acid plasma levels which increases urinary nitrogen excretion

• Synthetic Progestins II:

  • 21-carbon progesterone analogues

    • Antagonism: aldosterone-induced sodium retention

    • Slight androgenic/estrogenic effects

  • "19-nortestosterone", third-generation drugs:

    • Induce decidual endometrial stromal change

    • More effective gonadotropin inhibitors

    • Minimal androgenic/estrogenic/anabolic activity

• Clinical Uses: Progestins

  •  Therapeutic Uses

    • Major uses:

      • Hormone replacement treatment

      • Hormone contraception

  • Other Uses:

    • Induction of long-term ovarian suppression (large, parenteral does -- e.g.,medroxyprogesterone acetate) ® prolonged anovulation; amenorrhea

      • may be used to treat:

        •  Dysmenorrhea

        •  Endometriosis

        •  Hirsuitism

        •  Bleeding disorders (where estrogens -- contraindicated)

        •  Contraception

      • Significant problem: substantial delay before normal ovulatory function is regained

    • Medroxyprogesterone acetate: stop maturation in children with precocious puberty

      • Precocious puberty:

        • Definition:

          • Beast budding before age 8

          • Menarche before age 9

          • Developing sexual characteristics: appropriate for genetic/gonadal sex: isosexual percocity

          • Developing such characteristics: appropriate for opposite genetic/gonadal sex: heterosexual percocity

        • Cause:

          • early, otherwise normal sequence of pubertal development; with increase gonadotropin secretion and ovulatory menstrual cycles

          • Idiopathic (constitutional) precocious puberty: frequency -- 90%

          • 10% of cases: due to organic brain disease including:

            • Brain tumors

            • Encephalitis

            • Meningitis

            • Head injury

            • Neurofibromatosis

            • Tuberous sclerosis

    • Progestins: no role in treatment of threatened/habitual abortions

• Diagnostic Uses:  Progestins

  • Estrogen secretion testing

    • Administration of progesterone or medroxyprogesteronethat are withdraw bleeding in amenorrheic patients (only in estrogen-stimulated endometrium)

•   Contraindications,  Cautions and Adverse Effects:  progestins

  • Progestational compounds alone and in combination oral contraceptives, in some patients:

    •  Increase blood pressure

  • More androgenic progestins: reduce plasma HDL

• Other Ovarian Hormones

  • Testosterone

    • Small amount produced; importance uncertain

    • Ovarian androgen production increased during certain pathological states (hirsuitism and amenorrhea)

  •  Inhibin and Activin

    • Peptides: multi-dimeric forms

    • , subunits

      • subunit combination (inhibin): inhibits FSH secretion

      • subunit combination (activin): promotes emphasize secretion

    • Physiological roles: not fully elucidated

  • Relaxin

    • Peptide related to growth-promoting peptides; similar to insulin

    • Localization: ovary, blood, uterus, placenta

    • Relaxin synthesis: corpus luteal leutinizing granulosa cells

    • Physiological effects:

      •  Decrease uterine contractility

      •  Increase glycogen synthesis/water uptake by myometrium

      •  Changes mechanical characteristics of pubic ligaments/cervix, promoting delivery

• Hormonal Contraception

  • Overview

    • Oral contraceptive preparations contain:

      • Estrogens

      • Progestins

      • Estrogens and progestins

    • Two types of preparations for oral administration:

      • Estrogen/progestin combinations

      • Continuous progestin treatment (no concurrent estrogen administration)

      • Preparations for oral use: all well-absorbed

      • For estrogen/progestin combinations: neither drug alters pharmacokinetics of the other.

    • Implant Preparation:

      • Norgestrel -- effective ovulation suppressant; released from subcutaneous implants (norgestrel may also be utilized as progestin component of oral contraceptives preparation reprint

      • Medroxyprogesterone -- large dose, intramuscular injection leads to long duration contraception

• Pharmacological Effects

  •  Mechanism of Action: contraception

    • Estrogen/progestins: contraception by selective pituitary function inhibition leading to ovulation-inhibition

    • Combination agents (estrogen + progestins) cause change in cervical mucus

    • Combination agents (estrogen + progestins) produce motility and uterine tube secretion changes

    • *note: continuous use of progestins alone (effective contraceptive): does not always inhibit ovulation, i.e. other factors (above) are significant.

  •  Ovarian Effects

    • Combination agent/chronic use:

      • Ovarian function depression

      • Minimal follicular development

      • Absence of:

        • Corpus lutea

        • Larger follicles

        • Stromal edema

    • Following drug discontinuation: most patients (75%) on the late in first post-treatment cycle; 97% by the third post-treatment cycle

    • About 2% of patients remain amenorrheic for long periods (up to several years following contraceptive treatment)

  •  Uterine Effects

    • Following long contraceptive use:

      • Possible cervical hypertrophy; polyp formation

      • Cervical mucus changes (resembles postovulation mucus (thick/less copious)

    • Combination (estrogen/progestin) agents cause:

      • Stromal deciduation at cycle end

    • Combination agents containing (19-nor) progestins:

      • Increased glandular atrophy

      • Less bleeding

  •  Effects on the Breast:  estrogen-containing agents

    • Stimulation; some enlargement

    • Estrogen + estrogen/progestins combination ® lactation suppression

  • CNS Effects: estrogen-containing agents

    • Estrogen: increase in CNS excitation

    • Progestin: decrease in CNS excitation

    • Thermogenic effect (progesterone + synthetic progestins ® (possibly mediated in the CNS

  •  Endocrine Function:  estrogen/oral contraceptives

    • Change adrenal structure and function

    • Estrogens: increase corticosteroid-binding globulin concentration in the plasma

    • Changes in angiotensin-aldosterone system; increased plasma renin activity; increased aldosterone secretion

    • Increase in thyroxine-binding globulin;

      • Increased plasma thyroxine (T₄) levels

      • Increase SHBG levels (sex hormone-binding globulin)® decrease free androgen plasma levels

  •  Effects on Blood:  estrogens/oral contraceptives

    • Inconsistent alteration in blood coagulation times

    • Increase in factors VII, VIII, IX and X

    • Decrease in antithrombin III

    • Increase in coumarin derivatives amounts required to increase prothrombin time in patients on oral contraceptives.

    • Increase in serum iron/total iron-binding capacity

  •  Hepatic Effects:  estrogen/contraceptives

    • Changes in hepatic drug excretion/metabolism

    • Delayed clearance of sulfobromophthalein

    • Reduced bile flow

    • Increased cholic acid component in bile acids; proportion of chenodeoxycholic acid increased ® incidence of cholelithiasis

  • Lipid Metabolism Effects: estrogen/contraceptives

    • Estrogens: increase serum triglycerides, free and esterified cholesterol

    • Estrogens: increase phospholipids

    • Estrogens: increase high-density lipoproteins (HDL)

    • Estrogens: decrease low-density lipoproteins (LDL)

    • Estrogen effects seen at somewhat higher doses (i.e. 100 ug of mestranol or ethinyl estradiol; minimal effects at doses < 50 ug).

    • Progestins-- antagonizes these estrogen effects

  • Carbohydrate Metabolism Effects: estrogen/contraceptives

    • Effects similar to those observed in pregnancy

    • Decreased GI tract carbohydrate absorption

    • Progesterone: increases basal insulin; increases insulin rise induced by carbohydrates

    • Reduced carbohydrate tolerance associate with long-term potent progestin use, e.g. norgestrel -- (effect reversible)

  • Cardiovascular System Effects:estrogen/contraceptives

    • Higher systolic/diastolic blood pressure (usually slight)

    • Increased heart rate

    • Important to monitor blood pressure

  • Skin Effects:estrogen/contraceptives

    • Increased pigmentation (chloasma)

      • Enhanced by exposure to UV light

      • Enhanced in women with darker complexions

    • Androgen-like progestins: increased sebum; acne

    • Typical ovarian androgens suppression often leads to decreased sebum production and acne

• Clinical Uses

  •  Primary clinical use of combined estrogen/progestins: oral contraception

    • Small risk of conception (when these agents are used as directed)

    • Pregnancy rate (combination agents): 0.5-1 per 100 women years at risk

    • Factors contributing to contraceptive failure:

      • Phenytoin administration

      • Antibiotic administration

      • Missing doses

  • Other Clinical Uses:

    • Endometriosis Treatment

    • Severe dysmenorrhea -- major symptom

      • Estrogen therapy may induce painless periods; however this approach is often inadequate

      • Alternatively: long-term progestin dose or long-term progestin/estrogen doses prevents endometrial tissue periodic breakdown

•   Adverse Effects: Contraceptives

  • Introduction:  contraceptives

    • Low incidence of serious known toxicities

    • Intermediary metabolism changes -- reversible

    • A number of minor adverse effects

    • Remedies: change in formulation

• Mild Adverse Effects: contraceptives

  • Nausea, mastalgia, edema, breakthrough bleeding

    • Remedy:

      • Change preparation to one containing less estrogen

      • Change preparation one containing progestins with greater androgenic action

  • Changes in serum protein:

    • Consider when evaluating thyroid function, pituitary function, adrenal function test results

    • Increase sedimentation rates: secondary to increased fibrinogen levels

  • Headache

    • Typically mild/transient

    • Migraine: often worsened by treatment

      • May be associated with increased incidence of stroke

      • If migraine onset occurs during treatment -- discontinue treatment

      • If cerebrovascular accident occurs during treatment -- discontinue treatment

  • Withdrawal bleeding may fail to occur

•   Moderate Adverse Effects:  these effects may require discontinuation of oral contraceptive use

  • Breakthrough bleeding

    • Most common problem using progestational agent alone for contraception-- frequency = as many as 25%

    • More often seen in patients using low-dose agents compared to combination drugs with higher progestin/estrogen levels

  • Weight gain

    • More likely with combination drugs containing androgen-like progestins

    • Remedy: dieting/changing medication to one containing less progestin effect

  • Increase Skin Pigmentation

    • More common in dark-skinned women

    • Incidence increases with time:

    • 5% -- end of first-year

    • 40% -- after eight years

    • Worsened by vitamin D deficiency

    • Usually slowly reversible upon drug discontinuation

  • Acne

    • Worsened by androgen-like progestin containing contraceptives

    • Improved by contraceptives containing large estrogen content

  • Hirsuitism

    • Worsened by "19-nortestosterone" preparations/combinations

    • Remedy: use non-androgenic progestins

  • Ureteral dilation

    • Similar to that observed in pregnancy

    • Associated with bacteriuria

  • Vaginal Infection

    • More common

    • More difficult to managing patients taking oral contraceptives

  • Amenorrhea

    • Some patients remain amenorrheic for years after termination of oral contraceptives use; galactorrhea also observed

    • Prolactin levels: should be determined -- patient may have prolactinoma

• Severe Adverse Effects

  • Venous Thromboembolic Disease

    • Frequency (superficial/deep thromboembolic or disease not taking oral contraceptives) = 1 per 1000 woman years

    • Frequency -- low-dose oral contraceptives = 3 per 1000 woman years

    • Higher risk during first month of drug use then constant

      • Additional risk ends with cessation of contraceptive use

    • Predisposing factors that increase risk include:

      • Stasis, increased antithrombin III levels,injury, elevated homocysteinein

      • Genetic disorders that may increase venous thromboembolism include gene alterations influencing:

        • Levels of protein C (factor V Leiden), protein S, hepatic cofactor II

        • Family history: useful in identifying patients at risk

    • Venous thromboembolism incidence:

      • Depended on estrogen (not progestin) component of oral contraceptives

      • Unrelated to:

        • Age

        • Mild obesity

        • Cigarette smoking

      •  Contributing factors:

        • Reduced venous blood flow

        • Arterial/venous endothelial proliferation

        • Enhanced coagulation (reduced antithrombin III levels)

  •    Myocardial Infarction: contraceptives

    • Slightly increased risk in patients using contraceptives if the following risk factors are also present: (It is also possible that there is a basal, inherently increased risk independent of these factors)

      • Obesity

      • Hypertension/preeclampsia

      • Hyperlipoproteinemia

      • Diabetes

    • Significantly increased risk for smokers:

    • Risk: nonsmokers (women 30-40 years of age: 4 cases/100,000 users per year)

    • Risk: heavy-smokers (women 30-40 years of age:185 cases/1,000 uses per year)

    • Probable basis for increased risk:

      • Acceleration atherosclerosis (atherogenesis)

        • Decreased HDL

        • Decreased glucose tolerance

        • Increased LDL

        • Increased platelet aggregation

        • Possibly increased coronary vasospastic tendency

    • In combination oral contraceptives: progestational (i.e. progestin, androgenic) component decreases HDL levels; suggesting the particular risk may depend on the specific composition of the formulation used as well as individual patient's reaction

  •   Cerebrovascular Disease: contraceptive

    • Stroke risk: women >35 years of age; current users -- not previous users

    • Subarachnoid hemorrhage: increased both among current and previous users

    • Risk Estimates: approximately 37 cases/ 100,000 users per year

      • Fatality incidence: 10%; most subarachnoid hemorrhages

    • Risk Factors: hypertension

      • 3-6-fold increase in hypertension in women using oral contraception

    • Summary:  oral contraceptives increase risk of cardiovascular disorders at all ages, independent smoking status

      • Highest risk group: women > 35 years of age who are heavy smokers

  •   Gastrointestinal Disorders: contraceptive

    • Probable increased risk of cholestatic jaundice with progestin-containing oral contraceptives

    • More commonly observed in patients with a history cholestatic jaundice during pregnancy

    • Increase incidence of symptomatic gallbladder disease

      • Cholecystitis

      • Cholangitis

    • Possible increase risk of hepatic adenomas

    • possible increase risk of ischemic bowel disease (secondary to celiac and superior/inferior mesenteric arterial and venous thrombosis

  •   Depression: contraceptive

    • Incidence: 6% with some contraceptive formulations; they be necessary to discontinue treatment.

  •  Cancer:  contraceptive

    • Risk Reduction: endometrial/ovarian cancer

    • Lifetime risk: breast cancer may not be affected by oral contraceptive use.

    • Increase risk: possibly in younger women

    • Cervical cancer risk: uncertain/controversy

Primary Reference: Goldfien, A., The Gonadal Hormones and Inhibitors, in Basic and Clinical Pharmacology, (Katzung, B. G., ed) Appleton-Lange, 1998, pp 653-680.

Carr, B. R. and Bradshaw, K.D, Disorders of the Ovary and Female Reproductive Tract , In Harrison's Principles of Internal Medicine 14th edition, (Isselbacher, K.J., Braunwald, E., Wilson, J.D., Martin, J.B., Fauci, A.S. and Kasper, D.L., eds) McGraw-Hill, Inc (Health Professions Division), 1998, pp 2097-2115.

Mitchell-Leef, D.E. Endometriosis in Medicine for the Practicing Physician, Fourth edition, (Hurst, J. Willis, editor in chief) Appleton and Lange, 1996, pp 751-755.

 

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