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Flashcards in Pharmacology of Reproduction Deck (77):
1

Developing as a male or female

-A complex series of events triggered by sex chromosomes (XX vs. XY).
-Outside the gonads, male and female is mainly dependent upon levels of androgen hormones...
-Bi-potential organ precursors develop into male-specific (testosterone high) or female-specific (testosterone low) organs.
-Organs stay the same 30-40 days after conception-the the first hormonal surge comes and changes in gene expression actually determine male or female.
-Presence of a Y chromosome triggers male gonad development; testosterone and its metabolites trigger male-specific development outside the gonad.
-SRY gene on the male Y chromosome; when expression in Sertoli cells, triggers secretion of anti-Mullerian hormone, which is secreted from the Sertoli cells and causes regression of the Mullein ducts (develop into female anatomy).
-Simultaneously when the SRY gene is expressed in the Sertoli cells, the Leydig cells start to secrete testosterone and you get male-specific development (wolfing-duct development)
-Do not need any hormone signaling to develop as female.
-Female development is the DEFAULT path and does not require female hormones until puberty; occurs in the absence of androgens; Mullerian ducts develop and the Wolffian ducts degenerate.
-Male anatomical development depends on the androgen, testosterone, and its metabolites (DHT).
-It is important for women to avoid exposure to drugs that modify androgen signaling (especially during pregnancy); this could disrupt the gender development of the embryo in utero and into adulthood.

2

Anatomy and Histology-Males

-Testis
Site of reproductive cells and male sex steroid production.
Seminiferous tubules (site of spermatogenesis); sertoli cells, spermatogonia (early cell in the production of spermatozoa in the walls of seminiferous tubules).
Interstitial space between the seminiferous tubules; Leydig cells.

3

Anatomy and Histology-Females

Ovaries: site of reproductive cells and female sex steroid production.
-Granulosa cells
-Thecal cells
-18-22 weeks after conception is when he ovary has its peak number of primordial follicles; these decrease throughout development, remain basically dormant until puberty.
Primordial follicle-->primary follicle (fully grown oocyte)-->secondary follicle (start to get presumptive theca cells)-->early tertiary follicle-->graafian follicle (this forms if follicle goes on to maturation for ovulation-fluid filled sac)
-At any given time, you will have different stages of follicles within the ovary.

4

Synthesis of progestogens, androgens, and estrogens

-All steroid hormones are synthesized for cholesterol.
-Not all pathways to these hormones are separate pathways that start from cholesterol.
-They can be metabolized in both directions; what may start out as an androgen might end up as an estrogen; progestegin may e metabolized to an androgen or estrogen as well.
The synthesis of progestogens, androgens, and estrogens is closely intertwined; all 3 groups are steroid hormones derived from the metabolism of cholesterol.
-Progestogens activate the Progesterone Receptor; progesterone and a number of therapeutic synthetically altered progesterone derivatives.
-Androgens activate the Androgen Receptors; dehydroepiandrosterone (DHEA), androstenedione, testosterone, dihydrotestosterone (DHT), others.
-Estrogens activate the Estrogen Receptors (alpha, beta); 17beta-estradiol (most potent). estrone, and estriol (less potent), others (environmental estrogens).

5

Progestogens-what do they do?

-Progestogens generally exert anti proliferative effects on the female uterus: endometrium.
-Promote endometrial lining secretion rather than proliferation; promote the switch from proliferation to secretion.
-Progestogens are required for the maintenance of pregnancy.

6

Synthesis of Progestogens

Cholesterol --> Pregnenolone --> PROGESTERONE

7

Androgens-what do they do?

-Have masculinizing properties
-Testosterone is considered the classic circulating androgen; can be found in both men and women.
-DHT is the classic intracellular androgen; has a much higher affinity for the receptor (about 10x higher, although testosterone will bind to the receptor); produced at the target organ rather than circulating.
-Androgens required for conversion to a male phenotype during development.
-Required for male sexual maturation (development of sperm, sexual potency, male sexual function).
-Required for male reproductive functions.
Synthesis of Androgens:
Pregnenolone and Progesterone can be metabolized into androgen receptor ligands or androgens (DHEA, testosterone).

8

Testosterone

The major form of androgen in circulation.
Must be converted into dihydrotestosterone (DHT) in peripheral target tissues; done by 5-alpha-reductase.
-There are 3 different subtypes of 5-alpha-reductase (1, 2, and 3); they are expressed differently in different tissues
Action at the receptor:
-Testosterone can bind the androgen receptor.
-It has only modest affinity and modest androgenic activity.
-Converted in target tissues to the more active dihydrotestosterone (DHT); no DHT could lead to a problem in the male gonads.
MUTATIONS IN 5ALPHA-REDUCTASE-2 LEADS TO PSEUDOVAGINAL PERINEOSCROTAL HYPOSPADIUS!!! No drugs to reverse this; hard to surgicallyrepair because there is not enough of either tissue.

9

Estrogens-what do they do?

-Share a common feminizing activity; although they are expressed in both males and females.
-Estrogens are derived from the aromatization of precursor androgens.
The enzyme aromatse (Cyp19)
Ovary and placenta are most active.
Adipsoe tissue, hypothalamic neurons, and muscle synthesize aromatase; if you have more fat, you have more arrogates and more circulating estrogen.
Adipose tissue is the main source of estrogen in postmenopausal women and in aging men.
-Exogenous estrogens from food can be ingested and activate estrogenic pathways within the body.
Synthesis of Estrogens:
Start with cholesterol, then get DHEA which is an androgen; aromatase metabolizing androgenic precursors to estrone, estradiol and estriol.
-Aromatase can metabolize testosterone to estradiol; DHT can also be converted by another steroid enzyme to 3beta-A-diol (this is the most potent natural ERbeta ligand); an estrogenic compound that binds to ERbeta

10

Steroid Hormone Nuclear Receptors

Estrogen Receptor; estradiol
Androgen Receptor; testosterone
Progesterone Receptor; progesterone
Glucocorticoid Receptor; cortisol
Mineralocorticoid Receptor; aldosterone
-These receptors do have differences, but they are still very much the same; typical structures; makes difficult to target the bidding of just one or the other; cross-talk; differences in where receptors are expressed, can help with what is activated; these receptors do have specific ligands.

11

Steroid Hormone Action and Metabolism

-Superfamily of nuclear hormone receptors: progestogens, androgens, and estrogens, glucocorticoids, mineralocorticoids, vitamin D, and thyroid hormone.
-Transport- after synthesis, hormones diffuse into the bloodstream; a lot of the mare circulating.
-Bind to carrier proteins: sex-hormone binding globulin (SHBG); high affinity, low levels. AND Albumin; low affinity, high levels.
-Hormone ligands bind to receptor and dimerizes; recruits co-activators/co-repressors.

12

Progesterone Receptor

-Most progestins have significant cross-reactivity with androgen receptors.
-Prolonged progestin administration produces an androgenic effect.
-Most synthetic progestins used as drugs are modified to minimize their androgenic effects.

13

Estrogen Receptor

-Two types of estrogen receptors
Classical/genomic: ERalpha/ERbeta
Membrane/non-genomic: GPR30/ERalpha36; activates signaling cascades.
-Many actions of estrogens involve association of the receptor with other transcriptional cofactors.
Specific transcription cofactors are tissue- and ligand- dependent; why we have the SERMs.
Accounts for some of the target specificity.
AR and PR likely share these complexities.
-ER dimerizes, you can either have gene transcription, repression, or selective gene transcription.

14

HPG Axis: Hypothalamus-Pituitary

IMPORTANT IN DEVELOPMENT, REPRODUCTION, AND SEXUAL DIMORPHISM.
-Secretes gonadotropin-releasing hormone (GnRH)
-GnRH travels via the (hypophyseal) hypothalamic-pituitary portal system.
-Stimulates gonadotroph cells of the anterior pituitary gland.
-Pulsatile secretion of GnRH stimulates gonadotropin (LH,FSH) release from the anterior pituitary.
Continuous application of GnRH suppresses gonadotroph activity of cells in the pituitary gland, can be important in treatment in diseases like prostate cancer.
Important pharmacologic consequences in the administration of exogenous GnRH (chemical castration).
-Postive and negative feedback
-Production of GnRH, FSH, and LH is similar in both males and females; the effects on target tissues are different.

15

Pituitary target cells in males: Testis

LH
-Stimulates Leydig cells; when LH binds the receptor, inside the Leydig cell, cholesterol is metabolized into prenenolone and then to testosterone, which then diffuses out into the bloodstream or into the sertoli cell.
-The Sertoli cell can either use the testosterone or convert it to estradiol if there is binding of FSH to sertoli cell receptor.
-Increases the synthesis of testosterone
-Testosterone diffuses into neighboring Sertoli cells and the bloodstream.
FSH
-Stimulates Sertoli cells
-Increases the production of androgen binding protein (ABP); maintains high testicular concentrations of testosterone; necessary for spermatogenesis.
-Stimulates the production of other proteins necessary for sperm maturation.

16

Pituitary target cells in females: Ovaries (pre-ovulation)

FSH
-Stimulates Granulosa cells; stimulates aromatase and can convert androgen precursors to estradiol or other estrogens, which can then diffuse into the circulation.
-Increases production of ESTROGENS.
LH
-Stimulates Theca cells; activates a cascade of genes that allow for metabolism of cholesterol to androgenic precursors that then diffuse over to the granulosa cells.
-Increases production of ANDROGENS
-Androgens diffuse into neighboring Granulosa cells.
LH and FSH have different effects on the ovaries depending on where in the cycle the woman is.
Binding of both LH and FSH in the ovaries is required for production of estradiol.

17

Pituitary target cells in females: Ovaries (post-ovulation)

-Makes estrogens and progesterone
-In the granulosa cells, you have binding of both LH and FSH.
-Cholesterol is metabolized to progesterone and due to the FSH, estradiol is also produced from aromatase and androgenic precursors.
-LH still binds to the thecal cells.

18

HPG (Hypothalamic-Pituitary-Gonadal) axis: Feedback in males

-Testosterone produced in Leydig cells acts as a negative regulator of the pituitary gland and the hypothalamus.
-Sertoli cells synthesize and secrete inhibin, books synthesis and secretion of FSH.
-Sertoli cells synthesize and secrete activin: stimulates FSH release and does not affect LH.
Positive and negative feedback depending on how much FSH secretion is needed.

19

HPG Axis: Feedback in females

-Granulosa production of inhibins and activins; estrogen is more complex than testosterone in men; can involve either positive or negative feedback (depending on follicle stage).
-At ovulation, estrogen can increase the stimulation of FSH and LH.
-It can also inhibit LH, FSH, and GnRH secretion.
-Combination of estradiol and progesterone post-ovulation; synergistically suppresses GnRH, LH, FSH secretion; actions at both the hypothalamus and pituitary gland.
IN MALES, TESTOSTERONE INHIBITED GNRH, LH, AND FSH FOR NEGATIVE FEEDBACK.
IN FEMALES, ESTROGEN CAN DO BOTH NEGATIVE AND POSITIVE FEEDBACK.

20

Integration of endocrine control: the menstrual cycle

-Cycling of hormones
-Periodicity of 28 days; normal ranges of 24-35 days.
-Onset of puberty until menopause.

21

Menstrual Cycle Overview

-The portion of the menstrual cycle before ovulation is referred to as either the follicular or proliferative phase.
-Developing ovarian follicle produces most of the gonadal hormones (E2).
-When the follicle is developing, that is when you have the most production of estradiol.
-E2 stimulates cellular proliferation of the endometrium.
-The portion of the menstrual cycle after ovulation is referred to as the luteal or secretory phase.
-Corpus luteum produces progesterone!!
-Progesterone induces the endometrium to become secretory rather than proliferative!!!

22

Uterus-Proliferative Phase

-Follicles grow
-Estrogens increase
-Leading to proliferation

23

Ovulation

-Estrogen levels peak at the end of the proliferative phase.
-This peak of estrogen leads to a surge in LH and FSH levels.
-Results in eruption of follicles releasing the oocyte.
-A few hours after ovulation, the remaining follicle (granulosa and theca cells) change to lutein cells; they enlarge and are filled with lipid inclusions, yellow appearance=lutein cells.

24

Corpus luteum

-Cellular remains of the ruptured ovarian follicle.
-Secretes estrogen and progesterone, not just estrogen.
-Presene of progesterone signals the endometrium to switch from a proliferative to a secretory state.
-Endometrium begins synthesizing proteins for implantation of a fertilized egg.
-Blood supply to the endometrium also increases.
-Secretions from the endometrial glands are very important for the fetus during the first trimester of pregnancy.
-The reason for the switch in these hormones...prepare endometrium for implantation of a fertilized egg.

25

Uterus: Secretory (luteal) phase

-Corpus luteum produces progesterone and estrogen.
-This leads to decreased proliferation and increased secretion; uterine secretions are important for the embryo.
CORPUS LUTEUM
-If fertilization and implantation does not occur within 14 days...the corpus lute ceases production of estrogen and progesterone and the corpus lute regresses to form corpus albicans; looks like a scar on the ovary, a lot of it is broken down by macrophages.
-Absence of estrogen and progesterone:
Endometrial lining sheds and menstruation begins.
Pituitary inhibition removed, FSH and LH increase; this stimulates estrogen secretion and the development of new ovarian follicles and another cycle.
Uterus: Menstrual Phase: Not proliferating, not secretory, it just sheds its out lining and that is when menstruation starts.

26

Fertilization and Pregnancy

-Embryo secretes human chorionic gonadotropin (hCG); pregnancy test
-Corpus lute remains viable and secretes PROGESTERONE!!! Rather than regressing into the corpus albicans.
-Production of hCG decreases after 10-12 weeks of pregnancy and the placenta begins to secrete progesterone autonomously; no longer depends on the corpus luteum for progesterone secretion to stay viable.
Even though hCG secretion decreases after 10-12 weeks, it is still detectable in pregnancy tests, it is still more than normal; can detect hCG throughout pregnancy.

27

Pathophysiology of reproductive tract disorders

-Disruption of the hypothalamic-pituitary-reproduction axis; example: polycystic ovarian syndrome, prolactinoma.
-Common cause of infertility due to disrupted sex hormone production.
-Inappropriate growth of hormone-dependent tissue; examples: breast cancer, prostatic hyperplasia, prostate cancer, endometriosis, endometrial hyperplasia, leiomyomas (uterine fibroids).
-Decreased estrogen or androgen secretion: hypogonadism, menopause.

28

Polycystic ovarian syndrome (PCOS)

-Characterized by anovulation (failure of the ovary to release ova over a period of time generally exceeding 3 months) and increased levels of plasma androgen.
-Affects between 3-5% of women of reproductive age.
-Diagnosis is typically clinical; concurrent findings of anovulation and hirsutism because of increase in androgens (abnormal growth of hair on a person's face or body).
-Multiple etiologies are likely to be responsible for PCOS

29

LH hypothesis of PCOS development

-Observation of increased frequency and amplitude of pituitary LH pulses; 90% of women with PCOS have increased circulating LH; suggests that there is an increase in GnRH activity.
-No accompanied increase in FSH increases only the concentration of androgens, not estrogen!!
-Increased LH activity effects:
Stimulates ovary thecal cells to synthesize increased amounts of androgens: androstenedione and testosterone.
-INCREASED LH AND ANDROGEN LEVELS PREVENT NORMAL FOLLICLE GROWTH!!! This is dependent on estrogen.
Prevents follicle secretion of large amounts of estrogen.
Absence of estrogen "trigger" prevents LH surge and OVULATION.
-Patients with PCOS menstruate irregularly.

30

Insulin theory of PCOS development

-Observation that many women with PCOS are obese, insulin resistant, and secrete increased insulin.
-Increased insulin:
Decreases the production of sex hormone binding globulin (SHBG); helps transport sex hormones though the bloodstream.
Results in higher concentration of free testosterone; not being carried from metabolism site to their target.
Greater androgenic effects on peripheral tissues.
-Insulin directly synergizes with LH to increase androgen production of theca cells.

31

Ovarian Hypothesis of PCOS development

-Dysregulation of sex steroid synthesis at the level of the thecal cell.
-Abnormal increase in the activity of the oxidative enzymes for androgen synthesis at the thecal cell.
-Greater thecal cell production of androgens in response to any given stimulus; greater androgens are not converted to estradiol, no stimulus (FSH) to make this happen.
Dysregulation at the HPG axis.

32

PCOS: Common Treatments

-Target HPG:
Estrogen-progestin contraceptive to suppress LH and hence ovarian production of testosterone.
Side effects: clotting, weight gain.
-Target AR:
Spironolactone as an anti-androgen to block the masculinizing effects of testosterone.
-Target associated pathways:
Metformin, an anti-diabetic drug, decreases hepatic gluconeogensis leading to a decrease in insulin.
This treatment has been shown to increase fertility in women within weeks; however, because it is just targeting insulin portion and not androgenic effects, a lot of the reduction in hair, masculinizing effects take longer to effect and treat.
Regular ovulatory menses and normalization of testosterone levels.

33

Hyperprolactinemia

-Common cause of infertility among women of reproductive age.
-Clonal, benign tumors of lactotrophs in the anterior pituitary gland (prolactinoma).
High prolactin levels suppress GnRH release; reduces circulating levels of LH and FSH and estrogen as well.
Can also disrupt the growth of the gonadotrophs that are actually secreting LH and FSH and also decrease secretion this way as well.
Causes reductions in circulating LH, FSH, and estrogens.
-Prolactin-secreting tumors remain responsive to inhibitory effect of dopamine agonists: helps restore normal GnRH function.
Cabergoline or bromocriptine: suppresses prolactin secretion and decreases tumor size.

34

Inappropriate growth of hormone-dependent tissue: BREAST

These tissues require estrogen to grow.
Treatment of breast carcinoma expressing ERs includes use of agents to modify hormone signaling:
Pure antagonist (Fulvestrant)
Selective estrogen receptor modulator SERMs (Tamoxifn, Raloxifene); agonists in some cells and antagonists in others, dependent on cofactors or how the receptor is expressed.
Aromatase inhibitor (Anastrozole, Letrozole, Exemestane, Formestane); converts testosterone to estradiol.

35

Inappropriate growth of hormone-dependent tissue: PROSTATE

-Normal growth and maintenance of prostate tissue requires androgens.
-Once you hit puberty, there isn't a lot of proliferation; quiescent organ.
-Requires the local conversion of testosterone to dihydrotestosterone: occurs in the stream and basal cells of the prostate; need this to maintain normal size.
-Treatment of benign prostatic hyperplasia (BPH) and metastatic prostatic cancer includes androgen blockade:
5alpha-reductase inhibition (Finasteride, Dutasteride); decrease the growth the prostate because it needs androgens to grow
Receptor antagonism (Flutamide, Bicalutamide, Enzalutamide); block more potent androgen form from binding to the receptor itself.
-BPH occurs in almost every man over age of 80; normal process of aging.
GnRH agonists (Leuprolide); have initial surge in LH and FSH and initial surge in androgens, but if androgens constantly produced, have negative feedback; so much androgens being produced, start to suppress production of androgens through normal feedback group; used to treat prostate cancer.
Think of HPG axis in total.

36

Inappropriate growth of hormone-dependent tissue: ENDOMETRIOSIS

-Defined as the growth of endometrial tissue outside of the uterus
-Usually found in areas surround the fallopian tube: ovaries, rectovaginal pouch, and uterine ligaments.
-Endometriosis tissues respond to estrogen stimulation.
-Endometriosis grows and regresses with menstrual cycle: severe pain, abnormal bleeding, adhesion formation in peritoneal cavity because of excess growth of where this is supposed to be.
TREATMENT:
Endometriosis is usually estrogen-dependent.
Estrogen-progestin oral contraceptives.
Long half-life GnRH agonists; shut down HPG axis.
These tissues respond to estrogens; when estrogens are being produced, you see these effects.

37

Hypothesis of Endometriosis Origin

-Result from retrograde migration of endometrial tissue through the fallopian tubes during menstruation; when you have a lot of shedding during menstruation, a piece gets up into the fallopian tubes that then can cause this issue; they tissue is not supposed to be there.
-Result of metaplastic tissue growth from the peritoneum; tissue originating from the peritoneum.
-Result of spread of endometrial cells to extra-uterine site via lymphatic ducts.
-Result of increased aromatase activity in endometrial tissue that causes excess of growth.
This is how the tissue is SUPPOSED to function, it just isn't in the right place.

38

Decreased estrogen and androgen secretion-Hypogonadism

Impaired production of sex hormones before adolescence.
Patients DO NOT UNDERGO sexual maturation.
In puberty, there is no increase in sex hormone production; never enter puberty.
Hormone replacement can allow the development of secondary sexual characteristics; can help the development of the reproductive organs that occurs during puberty.
One of the few disorders that is treated by androgen replacement therapy.
Menopause-estrogen replacement; testosterone replacement is highly debated.

39

Decreased estrogen secretion: Menopause

-Normal physiologic response to exhaustion of the ovarian follicles.
-Menstrual cycles cease when all the follicles are depleted from the ovaries.
-Effects of follicle depletion:
Decreased estrogen production and inhibins
Results in an increase in LH and FSH because trying to increase estrogen production.
Androstenedione continues to be converted to estrone, just not estradiol (most potent form).
-Effects of relative lack of estrogen:
hot flashes, vaginal dryness, decreased libido, dermal atrophy, osteoporosis.
Estrone in ovaries postmenopausal is a less potent ligand, so the primary estradiol occurs mainly in fat tissues.

40

Decreased androgen secretion: age dependent changes in men

-Androgen secretion declines gradually with age
-Androgen therapy in normal elderly men is controversial.
-Androgen replacement is indicated in adult hypogonadism:
Low testosterone levels
Symptoms of hypogonadism
Not indicated in men undergoing the normal aging process; can cause prostate to grow and prostate disease.
Puberty-spike in testosterone
Fat tissue have aromatase; normal or slightly increased level of estrogen, muscles convert to fat; ratio of high testosterone and low estrogen switches to low testosterone and high estrogen; thought to be part of reason why men develop prostate disease.
Most men by 50, 50% of men develop BPH, increases to 90% of men in 90s.

41

Pharmacologic classes and agents

-Relevant drug classes:
Modulators of pituitary gland gonadotroph activity (LH/FSH production or GnRH secretion).
Specific antagonists of peripheral hormone action.
-Sex hormones: Replacement therapy: estrogens, androgens, progestogens.
Modify gonadotropin release from the pituitary gland (LH/FSH) to alter hormone levels.
-HPG-axis targets:
GnRH agonists: continuous: leuprolide, goserelin, nafarelin; can disrupt the entire process, GnRH usually released in pulses; can also have negative feedback from the pituitary to the hypothalamus with the continuous GnRH secretion.
GnRH receptor antagonists: cetrorelix, ganirelix
LIGAND/RC TARGET
-Aromatase inhibitors: exemestane, formestane, anastrozole, letrozole.
-Androgen receptor antagonists: flutamide, spironolactone; competitive inhibitors or selective antagonists (change conformation or recruit different cofactor to prevent binding to DNA).
-5alpha-reducatase inhibtor: finasteride; can decrease dramatically the activation of AR; one treatment for breast cancer
-SERMs; can decrease the ER response from Estrogen to gene transcription in the breast tissue and it has an opposite effect in the bone; aromatase converts testosterone to estradiol; different binding affinities to ER can be beneficial in treating disease because the different receptors have different effects: ERalpha drives disease whereas ERbeta more protects.
-Mifepristone-progesterone antagonist that blocks gene transcription at the level of receptor binding.
This all depends on what hormone you want to block in what tissue.

42

Synthesis Inhibitors: GnRH agonists and antagonists

-Mechanism of action
Normally the hypothalamus releases GnRH in a pulsatile fashion.
Frequency of GnRH pulses controls the release of LH and FSH.
Continuous administration of GnRH suppresses LH and FSH.

43

Synthesis inhibitors: GnRH agonists

Suppresses HPG axis
Continuous administration of Leuprolide, Goserelin, Nafarelin; overstimulation pituitary so the receptors so they are no longer sensitive to GnRH.
Used to suppress the HPG axis.
Desensitization of receptor; decrease LH and FSH being reduced.
Prostate cancer, some breast cancers, uterine fibroids, endometriosis, premature puberty.
Prevent premature ovulation (IVF), delay puberty for transgender.
Upon initial treatment, you have spike of LH, FSH=increased production of gonadohormones.
Also given AR receptor antagonist to prevent symptoms that come with this initial surge (for men with prostate cancer).
Symptoms: imitates menopause (hot flashes), men=castration conditions, no longer have maturation of sperm.

44

Synthesis Inhibitors: GnRH antagonists

Blocks the release of LH and FSH
Blocks GnRH binding to the receptor.
You do not have to wait for an initial spike in stimulation, effects are right away; block LH and FSH and gonadohormones immediately.
Immediate action without initial stimulation
Cetrorelix, Ganirelix

45

Synthesis inhibitors: 5alpha-reductase inhibitors

-Mechanism of action
Type 2 5alpha-reductase converts testosterone to dihydrotestosterone (DHT), this binds AR within the prostate.
Highly expressed in prostate stream and basal cells.
DHT is the main androgen receptor (AR) ligand in tissues.
5alpha-reductase inhibitors effectively remove the local action of androgens.
Reductase inhibitors slow the growth of prostate tissue and causes cell death.
Finasteride (type 2 5alpha reductase), Dutasteride (type 1 and type 2 5alpha-reductase)
-BPH
Improve symptoms of decreased urine flow (prevents progression).
One year treatment with finasteride can reduce prostate size up to 25%.
-Prostate cancer
Most effective for patients with larger prostates
Shrinking of prostate lead to better cancer detection? Higher chance of detecting the cancer?
-Adverse effects: decreased libido, erectile dysfunction.
Prostate has to be androgen sensitive and proliferation for this to inhibitor to work.

46

Synthesis Inhibitors: Aromatase Inhibitors

-Mechanism of Action
Estrogens are synthesized through the action of aromatase on androgen precursors
Can prevent recurrences
This treatment is only for cancers that are estrogen-dependent.
Blocking aromatase can effectively inhibit estrogen formation and growth of estrogen-dependent tissues.
-Clinical uses:
Treatment of metastatic breast cancer: postmenopausal only; because blocking all estrogen effects.
Aromatase inhibitors are slightly more effective than Tamoxifen for breast cancer.
Prevention of recurrences of cancers treated with surgery and radiation.
Andronstendione to estrone
Testosterone to estradiol
-Competitive Inhibitors: Anastrozole, Letrozole
-Covalently-bound inhibitors: Exemestane, Formestane
-Adverse Effects: profound suppression of estrogen action, fewer side effects than SERMs, increased risk of osteoporotic fractures, heart problems.
Completely ablating estrogen metabolism.
When the ER binds the ligand, it dimerizes, binds the estrogen response element, binds coactivators and activates gene transcription.
With antagonist: binds ER, recruits whole different set of cofactors and can either lock transcription or activate an entirely different set of genes.

47

Receptor Antagonists: Selective estrogen receptor modulators (SERMs)

-Mechanism of action:
Inhibit estrogenic effects in some tissues
Promote estrogenic effects in other tissues
Tissue-Deponent and coactivator dependent.
-Basis for SERM tissue selectivity:
2 main ER subtypes (ERalpha, ERbeta)
Expression of these receptor subtypes is tissue-specific; the coactivators that bind to either receptor is also tissue specific.
Ability of ER to interact with transcription cofactors depends on the structure of the ligand that is bound to the receptor.
IN THE BONE:
Have expression of cofactor X and cofactor Y
After ligand bind, receptor dimerizes, and cofactors X and Y bind, you have an agonist effect.
SERM can bind to receptor, only recruits coactivator X and only one part of gene is expressed-partial agonist.
IN THE BREAST
If only cofactor Y is expressed, you have expression of gene that cofactor Y targets, when you have SERM, does not allow for cofactor Y to bind, do not have any activation of transcription: no genes expressed.

48

SERMs: Tamoxifen

-Only SERM approved for use in the treatment AND prevention of breast cancer.
Raloxifine can be used for prevention.
-Used in the palliative treatment of metastatic breast cancer.
-Used as adjuvant therapy after lumpectomy.
-Selectivity:
ER antagonist in breast tissue
ER partial agonist in the endometrium
ER partial agonist in the bone.
-Effects:
Inhibition of the estrogen-dependent growth of breast cancer; if it is not estrogen dependent, tamoxifen will not due a lot.
Stimulation of endometrial growth.
-Tamoxifen is associated with a 4-6 fold increase in endometrial cancer.
-Tamoxifen is typically administered for no more than 5 years; switched to aromatase inhibitor.

49

SERMs: Raloxifene

-Selectivity
Estrogen receptor agonist in bone
Estrogen receptor antagonist in breast tissue
Estrogen receptor antagonist in endometrial tissue
-Effects:
Does no increase endometrial cancer
Decreases bone resorption (osteoporosis); prevents or slows down osteoporosis.
-Comparison of Raloxifene and Tamoxifen breast cancer prevention in high risk women (STAR trial):
-Both agents had 50% reduction in development of invasive breast cancer.
-Tamoxifen treatment was associated with more endometrial hyperplasia, endometrial cancer, cataracts, and deep vein thrombosis.
-Tamoxifen prevented more cases of non-invasive breast cancer.
Risk management

50

SERMs: Clomiphene

-Used to induce ovulation
-Selectivity
ER antagonist in the hypothalamus and anterior pituitary gland inhibiting negative feedback by E2 thus increasing GnRH; important for reproduction and sexuality/sexual development; a lot of ER in hypothalamus.
This SERM blocks this receptor activity in the hypothalamus.
-ER partial agonist in the ovaries.
-Effects:
Increased release of GnRH and gonadotropins
Increased levels of FSH stimulate follicle growth
Follicle gives the estrogen trigger signal, an LH surge, and ovulation=increasing ability to ovulate.
-Adverse effects: Can cause multiple follicles to grow resulting in an increased ovarian size; use is seldom associated with the ovarian hyper stimulation syndrome.

51

Receptor antagonists: androgen receptor

-Mechanism of action:
Competitively inhibit the binding of endogenous androgens to the AR; would not allow the AR to dimerize and translocate to the nucleus.
Block the action of testosterone and DHT; no activation by androgens.
-Flutamide, MDV3100 (Enzalutamide), Bicalutamide; used for the treatment of PROSTATE CANCER.
-Spironolactone
Originally approved as an aldosterone receptor antagonist.
Significant antagonist activity at the AR
Antagonize the excessive androgen stimulation of hair follicles (hirsutism).
-Drospirenone
Anti-androgen effects but also pro gestational (also could stimulate progesterone)
Used as a progestin in some estrogen-progestin contraceptives.

52

Progesterone Receptor antagonist: Mifepristone (RU-486)

-Competitive progesterone receptor antagonist used to induce first trimester abortion.
-Results in decay and death of the decidua.
-Lack of nourishment causes the blastocyst to die and detach from the uterus.
-Blastocyst no longer secretes hCG so the corpus lute involutes and stops producing progesterone.
-Involution of the corpus luteum decreases progesterone synthesis and secretion.
-Commonly administered in conjunction with Misoprostol (synthetic prostaglandin E1 analogue); used in conjunction gives about a 95% effectiveness in terminating first trimester pregnancies.
-Misoprostol stimulates uterine contractions.
-Adverse effects of Mifepristone (RU-486): given as a single dose so prolonged progesterone antagonism effects are rare.
-Main complication lies in excessive bleeding from the abortion.
-Adverse effects from Misoprostol: can cause nausea and vomiting.

53

Hormones and hormone analogues: Contraception

Estrogen/Progestin combinations; most common contraception.
-Suppresses GnRH, LH, and FSH secretion and follicular development; suppress HPG axis.
-Primary mechanism=inhibit ovulation.
-Most potent known way to suppress GnRH, LH, and FSH secretion without using something like a GnRH agonist or antagonist.
Works through some of the negative feedback loops.
-Secondary mechanisms: Inhibit proper transport of both egg/sperm (decrease fertilization), alterations in tubal peristalsis (if ovulate, oocyte might not enter fallopian tube as quickly), alterations in endometrial receptivity, alterations in cervical music secretions.
INHIBT OVULATION-NO MATURATION OF FOLLICLE THAT LEADS TO OVULATION; CAN ALSO ALTER OTHER MECHANISMS REQUIRED FOR FERTILIZATION THAT DECREASE CHANCE OF IMPLANTATION AND FERTILIZATION THAT LEAD TO PREGNANCY.
-Estrogens used:
Ethinyl estradiol, Mestranol
-Rationale:
Use of "unopposed" estrogens promotes endometrial growth.
Early estrogen-dominant contraceptives increase the risk of endometrial cancer.
Progestin is co-administered to limit the extent of endometrial growth.
-Progestin actions:
Potent progesterone recepto agonists
Almost all currently available progestins have some androgenic cross-reactivity.
-Progestins Used:
-Norgestrel, Levonorgestrel (highest androgenic activity)
-Norethindrone, Norethindrone acetate (lower androgenic activity)
-Etonogestrel, Ethynodiol, Norgestimate, Gestodene, Desogestrel (third generation progestins); even lower AR cross-reactivity.
-Drospirenone (synthetic progestin that also has anti-androgenic activity as opposed to AR cross reactivity).
Testosterone and a lot of androgens are converted from progestin precursors1!!!!! Structural similarity.
Combination therapy is important so you can look at how much AR activity you want to have; different potential side effects.

54

Contraception: Combination Estrogen-Progestin delivery system

-Vaginal ring
Consists of silastic cylinder packed with ethinyl estradiol and Etonogestrel.
Steroids release with zero-order kinetics (elimination is linear).
Ring is placed in the vagina for 21 days and then removed.
7 days following removal, menses may occur.
After 7 days, a new ring is inserted.
-Transdermal patches
Matrix that continually releases ethanol estradiol and Norelgestromin
The patch is changed weekly for 3 weeks.
During the fourth week, no patch is used and menses may occur.
-Oral tablets (21 days on, 7 days placebo).
7 day placebo period stimulates the physiologic involution of the corpus luteum; causes the endometrium to slough leading to menstruation.
Progestin inhibits endometrium proliferative growth (lighter menstruation).
Menstrual cycles often becomes more regular.
-Oral tablets (84 days on, 7 days placebo): Ethinyl estradiol and Levonorgestrel
Just as much efficacy is the 21-7, just decreases the number of menstrual cycles a women has if taking the 84-7.
-Oral tablets (24 days on, 4 days placebo)
Advantage: ovulation won't occur if patient forgets to start because it is just a 4 day placebo.

55

Contraception: Combination Estrogen-Progestin formulations

-Monophasic/contant dose (most common)
Standard formulation
Contant dose of estrogen and progestin for 21 days.
-Biphasic preparations
Constant estrogen dose throughout the cycle.
Progestin is initially low and then increases during the second half of the cycle.
-Triphasic formualtions
Levels change every 7 days
Increased progestin in the latter half of the cycle.
Mid cycle increase in the estrogen dose to prevent breakthrough bleeding.
-Quadphasic formualtions
Dienogest/Estradiol
Phasic preparations reduce the amount of hormone exposure; mimics biology of body much better.

56

Combination Estrogen-Progestin formulations

-Advantage of biphasic or triphasic administration:
Total amount of progestin administered over each month is reduced; do not want to give huge doses of the hormones.
Trend has been to decrease the administered estrogen and progestin amounts.
-No clearly established differences in adverse effects or efficacy in the four formulations; want to move toward lower doses, but no one has seen disadvantages between any of the 4 formulations.
Lowest ethinyl estradiol dose is preferred to reduce deep vein thrombosis; other than this, no adverse effects saying one is better than the other.
-Disadvantage of multi-phase pills compared to monophasic pills.
Trickier to take; if you skip, you can mess up the cycle due to differing hormone concentrations in the different pills.
Be careful not to start the next pack late: increased risk of pregnancy.

57

Combination Estrogen-Progesting ADVERSE EFFECTS

-Deep vein thrombosis and pulmonary embolism
-No demonstrated increase or decrease in breast cancer.
-Increase in gallbladder disease
Formation of gallstones; estrogens can increase the biliary concentration of cholesterol in bile salts.
-Should not be administered to women over 35 who smoke' increased thrombotic CV events.

58

Combination Estrogen-Progesting benefits

-Reduce endometrial cancer; first generation estrogen pills, you increase this risk.
Probably because constant progestin administration INHIBITS ENDOMETRIAL GROWTH.
-Reduce ovarian cancer
Probably by lowing circulating levels of gonadotropins (LH and FSH).
Overall, oral contraceptives much more beneficial effects than harmful effects; especially if your main objective is to prevent pregnancy.

59

Receptor Antagonists: Progesterone receptor antagonists

-Mechanism of action:
Progesterone is crucial for maintenance endometrium during pregnancy
Progesterone stabilizes the uterine lining.
Progesterone promotes vessel growth and secretory activities of the decidua.
Without progesterone, you do not get implantation or the maintenance of pregnancy; very important post ovulation and pregnancy; promote shedding of uterine lining.
-PR antagonists block these actions of progesterone.

60

Progestin-only contraception

-Continuous low-dose oral progestins
-Two progestin-only oral contraceptives available in the US: "mini-pill" and Norgestrel, Northindrone
-Prevents ovulation 70-80% of the time.
Probably because progestins alter frequency of GnRH pulsing.
Decrease anterior pituitary gland responsiveness to GnRH.
-This form of contraception is 96-98% effective: alterations in cervical mucus, endometrial receptivity, and tubal peristalsis.
-Progesterone inhibits endometrial proliferation and promotes endometrial secretion: egg may be unable to implant in endometrium continually exposed to progestin.
-Patients taking these drugs do not typically menstruate.
breakthrough spotting and irregular, light menstrual periods are common in first year.

61

Progestin-only contraception delivery preparations

-Injectables: Medroxyprogesterone acetate
Given every 3 months
Good for women who have difficulty remembering to take a pill or change a patch.
-Implants: Silastic implant
Releases Etonogestrel (progestin)
Effective for 3 years
Implant is typically inserted into the dorsal side of the forearm.
-Intrauterine device (IUD): Levonorgestrel
Liletta, Skyla (3 years-lowest dose of progestin in all 3 IUDs); Mirena (5 years).
The other IUDs have the same dose (Liletta and Mirena).
Localized effect, benefit is that you do not have other systemic effects.
Progestin only is more preferred than combination estrogen + progesterone therapy.
Only small amounts of hormone reaches the bloodstream.
Inserted by a physician.

62

Emergency (Morning-After) contraception

-Administration of medications to prevent pregnancy.
Failure of a barrier contraceptive
Recent unprotected intercourse (including sexual assault).
-Oral Levonorgestrel
Blocks LH surge disrupting normal ovulation
Produces endometrial changes that prevent implantation
Dose given as soon as possible after exposure and related in 12 hours.
-The morning after pull is the same as the IUD BC, but in a much higher dose.

63

Male contraception

GOAL: SUPPRESS ENDOGENOUS PRODUCTION OF SPERM REVERSIBLY!!!
Produce azoospermia (absence of sperm in the ejaculate)
Difficult because even 99% reduction would still leave a sufficient number.
-No suppression of libido or erectile function.
-Initial studies of male contraception used androgens.
-Administration of testosterone enanthate
Testosterone significantly suppresses gonadotropin release' reduced levels of LH and FSH are unable to stimulate Sertoli cell function=less sperm production.

64

Male Contraception Clinical Trials

-Suppression of spermatogenesis
Androgen and a progestin is superior to an androgen alone.
Combination more completely suppresses gonadotropin release!!!
-Combinations demonstrated to be effective REVERSIBLE male contraceptives:
Testosterone enanthate plus daily oral Levonorgestrel
Testosterone undecanoate plus Medroxyprogesterone acetate.
Clinical trial difficulties:
-Large population variability in the degree of spermatogenesis inhibition.
-On avergae, 60% of men become azoospermic.
-Significant adverse effects: acne, weight gain, potential increase prostate size.

65

Hormones and hormone analogues: Replacement

-Estrogens, progestins, and androgens are used as replacement therapies in cases of hormones deficiency.

66

Hormone replacement: Estrogens and Progestins

-Hormone replacement therapy; perimenopausal (shortly before the occurrence of menopause) and postmenopausal
-Principal indications: suppress hot flashes, treat urogenital tissues atrophy (vaginal dryness).
-Women's Health Initiative
Estrogen treatment:
Did not increase risk of coronary heart disease
Did not increase risk of breast cancer
Decreased risk of osteoporotic fracture
Increased risk of stroke and thromboembolism.
Continuous estrogen-progestin treatment:
Increased risk of CV events
Increased risk of breast cancer
Increased risk of stroke
Decreased risk of osteoporotic fracture.
-Current recommendations for postmenopausal women:
Use hormone therapy only to treat vasomotor symptoms (hot flashes, night sweats) or vaginal dryness.
Use lowest possible dose of hormone therapy for shortest period of time.
-Delivery systems
Oral tablets
Transfermal patches
Vaginal rings
-ESTROGEN TREATMENT IS NOT INDICATED FOR PRE MENOPAUSAL WOMEN; ONLY FOR TREATMENT OF MENOPAUSAL SYMPTOMS THAT ARE HARD TO LIVE WITH.

67

Hormone replacement: Men

-Androgens
Effective therapy for hypogonadism
Oral administration ineffective due to high first-pass metabolism by the liver.
-Injectable testosterone enanthate and testosterone cyprionate
Increases plasma testosterone to normal physiologic concentrations in hypogonadal men.
Injected intramuscularly every 2-4 weeks.
-Transdermal testosterone patches
Plasma testosterone levels remain relatively constant
First-pass hepatic metabolism is bypassed.
-Topical gel formulation
Once a day application schedule
Plasma testosterone levels gradually increase to physiologic levels over 1 month of application.
-Tablet
Adheres to buccal mucosa (mouth/cheek)
Results in rapid systemic absorption.

68

Hypogonadism in aging men

-Signs and symptoms:
Decreased energy, libido, muscle mass, facial hair growth.
Gynecomastia (enlarged breasts in men).
-Recent guidelines for replacement therapy
Consistent signs and symptoms with low plasma testosterone levels (<3.0 ng/mL).
-Testosterone SHOULD NOT be administered to men with prostate cancer; will complicate cancer.

69

Abuse of androgenic/anabolic steroids

-Anabolic steroids are schedule 3 controlled substances and are illegal to use or distribute without a prescription or license.
-Bodybuilders and athletes use them for enhanced performance (strength, muscle mass, recovery from hard efforts).
-Others use them to improve their appearance/physique.

70

Androgen Abuse

-Some athletes abuse androgens with supra therapeutic levels.
Demonstrated to increase muscle mass and fat-free mass.
5% of high school athletes reported they had used androgen supplements.
-Almost every type of androgen has been abused; not just talking about androgens and DHT
Adrenal precursors androstenedione and dehydroepiandrosterone
New "designer androgens
-Increase androgens in the body, you can increase the amount of estrogens; not just adding one compound, you can potentially effect a lot of symptoms.

71

Important side effects of anabolic steroids

-CV problems including increased LDL/HDL ratio and hypertension.
-Liver damage
-Cancer risk increased
-Male infertility; decreased fertility can be due to negative feedback with increased androgens.
-Acne
-Increase in plasma estrogen resulting in gynecomastia
-Mood/behavior changes
-Erthyrocytosis (increase number of circulating RBC) and derangements in lipid metabolism.
-Likely causes early mortality (many premature deaths among known or suspected steroid users).

72

Modeling anabolic steroid abuse

-Treatment in male mice modeled use in young adults with cessation in middle age.
-Increase in premature deaths was DOSE DEPENDENT.
-The highest dose had the lowest percent surviving, then low dose, then control.

73

Sexual Dysfunction-Erectile Dysfunction-CAUSES

-Hypertension
-Diabetes
-CV disease
-End-stage renal disease
-Nerve disorder
-Psychological factors (stress, depression, performance anxiety)
-Drugs (beta blockers, anti-androgens, estrogens).

74

Normal male sexual response

Stimuli
Parasympathetic nervous system releases NO at nerve terminals near blood vessels in the penis.
Signal transduction cascase is activated that includes activation of guanylate cyclase to generate cyclic GMP.
Vasodilation increase blood flow into the erectile tissue (until the tunica albuginea becomes stretched and the organ turgid).
Smooth muscle of the helicine arteries is the driving force.

75

Regulation of erection

-NE through alpha-adrenergic receptor increases intracellular calcium and inhibits potassium channels: smooth muscle contraction.
-Prostaglandin E1 (PGE1) stimulates potassium channels and decreases intracellular calcium: smooth muscle relaxation.
-Nitric oxide stimulates synthesis of cGMP which stimulates potassium channels and decreases intracellular calcium: smooth muscle relaxation.
RELAXED MUSCLE=ERECTION

76

Drugs for ED

-Phosphodiesterase 5 (PDE5) inhibitors:
Mechanism of penile erection involved cGMP as a second messenger in smooth muscle of the helicine arteries.
The male sexual response is down-regulated by a process that includes destruction of cGMP by PDE5=ED.
PDE5 inhibitors (Sildenafil, Tadalfil, Vardenafil) promote penile erection by blocking destruction of cGMP in the helicine arteries.
-Viagra (Sildenafil); could increase blood flow to the FEMALE reproductive tract.
First effective oral agent (1998)
Effect observed after 30-60 minutes.
Metabolized after 8 hours.
-Levitra (Vardenafil)
Similar rate of uptake and metabolism as Sildenafil
-Cialis (Tadalfil)
Slower uptake (60 minutes)
Longer duration of action (36 hours).
Vardenafil (livetra) has the same uptake as Sildenafil (viagra)
Side effects and contraindications
-Headache, flushing, respiratory tract disorders.
-Should not take nitrates until 24 hours after use (>36 hours for Tadalafil, longer duration of action).
-Sildenafil affects clearance of coumadin and tolbutamide: cimetidine and erthromycin affects clearance of sildenafil.
-Vardenafil and Tadalafil clearance affected by erthyromycin.

77

Female sexual dysfunction

-Associated with variety of diseases or conditions (particularly estrogen deficiency) and psychological factors:
Depression
Anxiety
Stress
Hormone deficiency (menopause, endocrine disorders).
Vaginal atrophy
Diminished vaginal/clitoral blood flow.
Treatment:
-Estrogens
Systemic treatment (high doses estrogen/progestin)
Benefits not limited to sexual function (relief of hot flashes, bone loss, improved sleep)
Risks include venous thrombosis, stroke, breast cancer.
Local/topical treatment
Vaginal estrogen cream (Premarin, Esterase, Ogen); low doses of estrogen, slow release, continuous, daily.
Vaginal Estrogen Ring (Estring); 3 months efficacy
Vaginal tablets (Vagifem)
-Flibanserin (Addyi)
FDA approved drug initially developed as an anti-depressant
Treatment of premenopausal women with hypoactive sexual desire disorder
Risk of serious hypotension and syncope especially in patients with hepatic dysfunction or normal patients on medications that inhibit CYP3A4.
-Flibanserin is an agonist for serotonin receptors and partial agonist for dopamine receptors; ot widely used although it helps.
-Viagra could increase blood flow to female reproductive tract.