Drugs Used In Disorders of the Reproductive System

Photo: Color-enhanced scanning electron micrograph of a human oocyte. From: Seeley’s Anatomy & Physiology 10th ed New York, NY: McGraw-Hill 2010

Marc Imhotep Cray, MD
Learning Objectives
PHARMACOLOGY OF GONADAL HORMONES:
1. ESTROGENS AND PROGESTINS
1. The physiological actions and pharmacological effects of estrogens and
progestins that are relevant to their clinical uses.
2. The adverse effects and contraindications of estrogens and progestins.
3. The current strategies for the use of estrogens and progestins in oral
contraceptives and in hormone replacement therapy in menopause.
4. The pharmacological actions and clinical uses of Selective Estrogen
Receptor Modulators (SERMs).
2. ANDROGENS
1. The physiological actions, pharmacological effects, and clinical uses of
androgens.
2. The adverse effects and contraindications to use of androgens.
3. The pharmacology and clinical uses of androgen antagonists.
2

Topical Outline
3
 Organization and Function of Reproductive System
 Reproductive Pharmacology Overview
 GnRH, Gonadotropins and Related Agents
 Sex (Gonadal) Hormones and Antagonists
 Contraception
 Endometriosis and Treatment
 Combination Oral Contraceptives, and Progestin
 Postmenopausal Hormone Changes and Therapy
 Selective Estrogen Receptor Modulators and Antiestrogens
 Hypogonadism

Gonadotropins & Related Drugs
4
Follicle-stimulating hormone (FSH)
Luteinizing hormone (LH)
Chorionic gonadotropin
Choriogonadotropin alfa
Follitropin alfa
Follitropin beta
Urofollitropin
GnRH analogs
Leuprolide
Goserelin
Histrelin
Ganirelix

Sex hormones & Related Drugs
ESTROGENS
Estradiol USED IN MANY COMBINATIONS
Estrone
Ethinyl estradiol USED IN MANY COMBINATIONS
Mestranol (w/norethindrone)
SELECTIVE ESTROGEN-RECEPTOR
MODULATORS (SERMs)
Clomiphene
Raloxifene
Tamoxifen
PROGESTOGENS cont.
Norethindrone
Norethindrone acetate
Norgestimate USED IN MANY COMBINATIONS
Norgestrel (w/ethinyl estradiol)
Progesterone USED IN MANY COMBINATIONS
Toremifene
Dienogest (w/estradiol valerate)
Etonogestrel (w/ethinyl estradiol)
Etonogestrel (subdermal)
PROGESTERONE AGONIST/ANTAGONIST
Ulipristal acetate
PROGESTOGENS
Desogestrel USED IN MANY COMBINATIONS
Drospirenone (w/ethinyl estradiol)
Levonorgestrel
Medroxyprogesterone
Norelgestromin (w/ethinyl estradiol)
5

Sex hormones & Related Drugs cont.
PROGESTERONE ANTAGONIST
Mifepristone
ANDROGENS
Danazol
Fluoxymesterone
Methyltestosterone
Oxandrolone
Oxymetholone
Testosterone
Testosterone cypionate
Testosterone enanthate
ANTIANDROGENS
Bicalutamide
Dutasteride
Finasteride
Flutamide
Nilutamide
6

Key Definitions & High-Yield Terms to Learn
7
 Androstanes: any 19-carbon steroid hormone, such as testosterone or
androsterone, which controls the development and maintenance of male
secondary sex characteristics
 Estranes: any 18-carbon steroid hormone, such as estradiol and estrone,
produced chiefly by ovaries and responsible for promoting estrus and
development and maintenance of female secondary sex characteristics
 Pregnanes: any 21-carbon steroid hormone, such as progesterone, responsible
for changes associated with luteal phase of menstrual cycle, differentiation
factor for mammary glands
 Cytochrome P450, CYP: any of a large number of enzymes produced from
cytochrome P450 genes, are involved in synthesis and metabolism of various
molecules and chemicals

Marc Imhotep Cray, MD 8
Biosynthesis of steroids
Enzymes with prefix CYP represent mitochondrial
cytochrome P450 mixed function oxidases, and numbers
indicate site of steroid hydroxylation.
Steroids indicated in bold are primary secreted steroids.
Lynn Wecker et.al. Brody’s Human Pharmacology: Molecular to Clinical, 5th Ed. Philadelphia: Mosby, 2010
P450scc
Steroid metabolism (steroidogenesis)

Key Definitions & Term cont.
 Nuclear receptor: A superfamily of receptor molecules that are activated by
steroid hormones, fatty acid derivatives, or products of metabolism such as
bile acids. They act by altering rate of transcription of specific target genes.
 HREs: Hormone response elements. specific nucleotide sequences, residing
upstream of steroid target genes, that are bound by steroid hormone receptors
 ERE: Estrogen-response element. A DNA sequence motif that binds estrogen
receptors. Consensus sequence is GGTCANNNTGACC.
 PRE: Progesterone-response element. A DNA sequence motif that interacts
with progesterone A or progesterone B receptors.
 SERM: Selective estrogen receptor modulator. A group of drugs that display
tissue specific estrogen agonist or antagonist activity. 9

10
Transcriptional regulation by intracellular steroid hormone receptors.
Whalen K. Lippincott Illustrated Reviews: Pharmacology, 6th Ed. Philadelphia, PA: Wolters Kluwer, 2015;352.

11
 5α-Reductase The enzyme that converts testosterone to
dihydrotestosterone (DHT)]
 5α-Reductase is inhibited by finasteride, a drug used to treat
benign prostatic hyperplasia (BPH) and prevent male-pattern
hair loss in men
 Anabolic steroid Androgen receptor agonists used for anabolic
effects (e.g., weight gain, increased muscle mass)
 Breakthrough bleeding Vaginal bleeding that occurs outside of
period of regular menstrual bleeding

12
Combined oral contraceptive (COC or just OC) Hormonal
contraceptive administered orally that contains an estrogen and a
progestin
Hirsutism A male pattern of body hair growth (face, chest, abdomen)
in females that results from hyperandrogenism
HRT (Hormone replacement therapy) refers to estrogen
replacement for women who have lost ovarian function and nearly
always involves combination therapy with estrogen and a progestin

Organization of Reproductive System
14
Sex (gonadal) hormones include progestins, estrogens, and
androgens
 Produced by gonads and adrenal glands
 necessary for conception, embryonic maturation, and development of
primary and secondary sexual characteristics
One example of these functional gonadal relations is menstrual
cycle: menstrual cycle is controlled by a neuroendocrine cascade
involving hypothalamus, pituitary, and ovaries
 hypothalamus releases gonadotropin-releasing hormone (GnRH) triggers
anterior pituitary to release gonadotropins, luteinizing hormone (LH) and
follicle-stimulating hormone (FSH) with effects on ovaries
o N.B. Understanding menstrual cycle provides a basis for understanding
pharmacology of contraception

Organization of Reproductive System (2)
15
 Androgens are steroids w anabolic and masculinizing effects in
both males and females
 Testosterone, main androgen in humans, is synthesized and
secreted primarily by testicular Leydig cells, as well as by ovaries
in women and by adrenal glands
 Testosterone secretion is also controlled by hypothalamus-
pituitary-gonad cascade

16Raff RB, Rawls SM, Beyzarov EP. Netter's Illustrated
Pharmacology, Updated Edition. Philadelphia: Sanders, 2014
Microanatomy: Using Testis As Example
 Seminiferous tubules (3 cell types)
 Spermatogonia (germ cells) Line seminiferous
tubules; Maintain germ pool and produce 1°
spermatocytes
 Sertoli cells (non–germ cells) Line seminiferous
tubules Secrete inhibin B inhibit FSH; Secrete
androgen-binding protein maintain local levels of
testosterone; Convert testosterone and
androstenedione to estrogens via aromatase;
Homolog of female granulosa cells
 Leydig cells (endocrine cells) Interstitium Secrete
testosterone in presence of LH; Homolog of female
theca interna cells
Organization of Reproductive System (3)

17
Regulation of Estrogen and Testosterone
Estrogen is synthesized in several forms, estradiol, estrone and estriol
 Potency: estradiol > estrone > estriol
Many organs and processes in women are under influence of estrogen
menstrual cycle shows its greatest effects
 For control of cycle hypothalamus periodically (pulsatile) releases GnRH
 triggers anterior pituitary to release gonadotropins= LH and FSH
 LH and FSH, are responsible for growth and maturation of ovarian follicles
o also control ovarian production of estrogen and progesterone
• exert feedback regulation on pituitary and hypothalamus and signal
them when to start and stop releasing GnRH, FSH, and LH

Regulation of Estrogen and Testosterone (2)
18
 In males, hypothalamus and anterior pituitary also effect release
of FSH (starts spermatogenesis) and LH (triggers steroidogenesis
in Leydig cells)
 Testosterone resulting from steroidogenesis inhibits hormone
production via negative feedback on  pituitary and
hypothalamus, and  release of GnRH, FSH, and LH ends

Regulation of
Estrogen and
Testosterone (3)
19
Raff RB, Rawls SM, Beyzarov EP. Netter's Illustrated Pharmacology, Updated Edition.
Philadelphia: Sanders, 2014

Events of Normal Menstrual Cycle
20
Understanding menstrual cycle provides a basis for understanding pharmacology of
contraception
 Start of cycle, cycle day 1, is arbitrarily defined as first day of
menstruation
In follicular (or proliferative) phase, hypothalamus releases GnRH
triggers anterior pituitary to release LH and FSH
 These gonadotropins cause graafian follicle to mature and secrete estrogen
 Estrogen inhibits pituitary it reduces gland’s release of LH and FSH
(negative feedback loop)
 In midcycle, however, estrogen triggers a surge in gonadotropin
release (LH surge) from pituitary (a brief positive feedback effect),
which stimulates follicular rupture and ovulation
 Ruptured follicle becomes corpus luteum produces progesterone and
estrogen under influence of LH during second half of cycle (luteal phase)

Events of Normal Menstrual Cycle (2)
21
Luteal (or secretory) phase
 Progesterone promotes development of a secretory
endometrium that can accommodate embryo implantation
 Conception causes progesterone secretion to continue with
endometrium maintained as suitable for pregnancy
 Without conception corpus luteum stops progesterone release
and ceases to function hormone levels decrease and
menstruation begins

22
Events of Normal
Menstrual Cycle (3)
 28 days (normal range, 24–35 days)
 Follicular phase can vary in length
 Luteal phase is 14 days
 Ovulation day + 14 days = Menes
 Follicular growth is fastest during 2nd
week of follicular phase
 Estrogen stimulates endometrial
proliferation
 Progesterone maintains endometrium
to support implantation
 ↓Progesterone ↓fertility Le T and Bhushan V. First Aid for the USMLE Step 1 2016 . McGraw-Hill 2016.

23
Developing follicle
The Oocyte and Ovulation
Stages of oocyte development and ovulation
Smith PR & Turek PJ. The Netter Collection of Medical Illustrations: Reproductive System, Volume 1, 2nd Ed. Philadelphia, PA: Saunders-Elsevier, 2011

24
Smith PR & Turek PJ. The Netter Collection of Medical Illustrations: Reproductive System, Volume 1, 2nd Ed. Philadelphia, PA: Saunders-Elsevier, 2011

Menstrual cycle capsular summary:
 Menstrual cycle is divided into follicular phase and luteal phase
Ovulation defines transition between these two phases
 During follicular phase, gonadotroph cells of anterior pituitary gland
secrete LH and FSH in response to pulsatile GnRH stimulation
 Circulating LH and FSH promote growth and maturation of ovarian follicles
 Developing follicles secrete increasing amounts of estrogen
 At first, estrogen has an inhibitory effect on gonadotropin release Just
before midpoint in menstrual cycle, however, estrogen exerts a brief
positive feedback effect on LH and FSH release This is followed by
follicular rupture and release of an egg into fallopian tube
 During second half of cycle, corpus luteum secretes both estrogen and
progesterone
 Progesterone induces a change in endometrium from a proliferative to a
secretory type
 If fertilization and implantation of a blastocyst do not occur within 14 days
after ovulation corpus luteum involutes secretion of estrogen and
progesterone declines, menses occurs, and a new cycle begins
Cairo CW, Simon JB, Golan DE. (Eds.). Principles of Pharmacology:
The Pathophysiologic Basis of Drug Therapy. LLW, 2012.

Menstruation terminology
26
 Dysmenorrhea= Pain with menses often associated with
endometriosis
 Oligomenorrhea > 35-day cycle
 Polymenorrhea < 21-day cycle
 Metrorrhagia= Frequent or irregular menstruation
 Menorrhagia= Heavy menstrual bleeding > 80 mL blood loss or > 7
days of menses
 Menometrorrhagia= Heavy, irregular menstruation

Reproductive Pharmacology Overview
28
 A number of diseases are treated pharmacologically via
modification of reproductive hormone activity ranging
from infertility and endometriosis to breast and prostate cancer
 Key concepts in this presentation will include:
1. Interactions between estrogen and pituitary gland
2. Effects of GnRH release frequency on gonadotropin release
3. Tissue selectivity of estrogen receptor agonists and antagonists
4. Strategies used to antagonize effects of endogenous sex
hormones from suppression of hypothalamic-pituitary-
gonadal axis to antagonism at target tissue receptor

Reproductive Pharmacology Overview (2)
 Sex hormones include androgens, progestins, and estrogens
 produced by gonads and adrenal glands (smaller quantities)
 They are necessary for:
 Conception
 Embryonic maturation, and
 Development of primary and secondary sexual characteristics
during puberty
 Sex hormones are used therapeutically
 as contraceptives
 as therapy for menopausal Sx & postmenopausal complications
 as replacement therapy in hypogonadism
 several antagonists are effective in cancer chemotherapy
29

Reprod Pharm Overview (3)
30
 Risks & benefits of estrogen postmenopausal w regard to
 cardioprotection
 neuroprotection, and
 carcinogenicity
are a subject of much debate and considerable research
 Certain hormone-like drugs whose estrogenic activities are tissue
selective (selective estrogen receptor modulators or SERMs) have
different therapeutic uses, including
 prevention and treatment of breast cancer (tamoxifen) and
 osteoporosis (raloxifene)

Reprod Pharm Overview (4)
31
 Infertility associated with anovulatory menstrual cycles can be
treated by use of antiestrogens such as clomiphene
 In female patients with failure of ovarian development,
therapy with estrogen, usually in combination with progestin,
replicates most of the events of puberty
 Testosterone replacement therapy is used for male patients
with hypogonadism
 Anti-androgens (flutamide) are used to treat androgen-
dependent cancers such as prostate carcinoma

Overview (5) reprod. pharm HY facts cont.
Ways to achieve androgen deprivation
32
The four ways to achieve androgen deprivation are:
1. Inhibition of pituitary gonadotropin release: GnRH analogs
(leuprolide)
2. Inhibition of androgen synthesis: aminoglutethimide,
ketoconazole, finasteride
3. Inhibition of androgen binding: androgen receptor blockers
(flutamide and others)
4. Surgical extirpation of glands: castration and adrenalectomy

Functional Gonadal Relations
34
3 gonadotrophic hormones of pituitary adenohypophysis
(1)follicle-stimulating hormone (FSH)
(2) luteinizing hormone (LH) of the female, known as
interstitial cell–stimulating hormone (ICSH) in male, &
(3)luteotropin (prolactin, LTH)
These pituitary hormones determine development of
M and FM gonads

 Germinal epithelia of testes and
ovaries are responsible for production
of sperm and ova, respectively
 Various stromal cells of gonads are
responsible for production of androgen
and estrogen hormones, which act on
organs of reproductive tract, secondary
sex organs, and other parts of body
 There is a feedback loop for
interdependent regulation of
production of gonadal and pituitary
hormones (See next slide)
Functional Gonadal Relations (2)
Raff RB, Rawls SM, Beyzarov EP. Netter's Illustrated

Negative and Positive Feedback Regulation
In most cases, a hypothalamic– pituitary–target gland
axis is regulated by negative feedback whereby tropic
hormone of anterior pituitary gland  negative
feedback effects on hypothalamus  target gland
hormone has negative feedback effects on both
hypothalamus and anterior pituitary
 By way of these mechanisms levels of target gland hormone
are maintained within normal physiological range
36

Negative and Positive Feedback Regulation (2)
 Positive Feedback
 Although negative feedback is primary homeostatic mechanism
in endocrine system, rare examples of positive feedback exist
 Prime example of positive feedback occurs during
menstrual cycle
 In late follicular phase of cycle, estradiol levels rise above a
critical point above which positive feedback occurs
o High estradiol concentration results in a surge in
hypothalamic secretion of GnRH and pituitary secretion of
LH (called LH surge) and FSH inducing ovulation
• Ovulation and transformation of ovarian follicular cells into corpus
luteum signals end of positive feedback 37

Negative and
Positive Feedback
Mulroney SE & Myers AK. Netter's Essential Physiology 2nd Ed. Philadelphia: Elsevier, 2016.
38

Gonadotropin-releasing hormone (GnRH)
39
 A decapeptide produced by neurons in preoptic area of hypothalamus
 Pulsatile secretion of gonadotropin-releasing hormone (GnRH) from
hypothalamus is essential for release of gonadotropins-- follicle stimulating
hormone (FSH) and luteinizing hormone (LH) --from anterior pituitary
however,
 Continuous administration of GnRH inhibits gonadotropin release through
down-regulation of GnRH receptors on pituitary
 Continuous admin. of synthetic GnRH analogs, such as
o leuprolide
o goserelin
o nafarelin
o Histrelin
effective in suppressing production of gonadotropins
• Several are available as implantable formulations that provide
continuous delivery of drug

Gonadotropin-releasing hormone (2)
40
 Suppression of gonadotropins  leads to reduced production of gonadal
steroid hormones (androgens and estrogens)
Uses
Thus, these agents are effective in treatment of
 prostate cancer
 endometriosis, and
 precocious puberty
Adverse effects
 In women, GnRH analogs may cause hot flushes and sweating, diminished
libido, depression, and ovarian cysts
 In men, initially cause a rise in testosterone that can result in bone pain
 Hot flushes, edema, gynecomastia, and diminished libido may also occur
Contraindications
 Agents are contraindicated in pregnancy and breast-feeding

Gonadotropin-releasing hormone agonists
41
 Gonadotropin-releasing hormone agonists (eg., leuprolide,
goserelin) create a temporary medical oophorectomy by
causing paradoxical effects on pituitary:
  initial stimulation of LH and FSH release and
  then (w continuous admin.) inhibition of hormone release
o Effects result in reduced sex hormone levels and
regression of endometriosis-related lesions
 Long-acting formulations are usually given every 28 days for
approximately 6 months
N.B. Remember that pulsatile administration of
exogenous GnRH stimulates gonadotropin release,
whereas continuous GnRH administration inhibits LH
and FSH release and thereby blocks target cell function.

Raff RB, Rawls SM, Beyzarov EP. Netter's Illustrated Pharmacology, Updated Edition. Philadelphia: Sanders, 2014

Gonadotropin-releasing hormone agonists (2)
43
 GnRH agonists are contraindicated in pregnancy
 GnRH agonists have hypoestrogenic side effects, eg, mild
bone loss (reverses after drug is stopped)
 b/c of concerns about osteopenia, add-back low-dose
estrogen therapy has been used

Gonadotropin-Releasing Hormone Antagonists
44
 Ganirelix, cetrorelix, and degarelix are synthetic peptides that act as
competitive antagonists at GnRH receptors
 They dose-dependently inhibit secretion of FSH and LH
 Ganirelix and cetrorelix are used to inhibit premature LH surges in women
undergoing ovarian hyperstimulation as part of infertility treatment
 Degarelix is indicated for treatment of advanced prostate cancer in men
o By blocking pituitary GnRH receptors, inhibits secretion of
gonadotropins and subsequent release of testosterone appears to
be mechanism for suppression of cancer
Absolute Contraindications
 All agents absolutely contraindicated for use during pregnancy (Category X)
See U.S. FDA “CAT” System (Drug Use in Pregnancy Categories)
Adverse Effect
 major AE is hypersensitivity or allergic reactions, including anaphylaxis

Question
45
A 75-year-old man had surgery for prostate carcinoma, and local
metastases were found intraoperatively. What is the most
appropriate follow-up drug aimed at treating the metastases?
A. Aminoglutethimide
B. Fludrocortisone
C. Leuprolide
D. Mifepristone
E. Spironolactone

Answer
46
Correct Answer is C. Leuprolide a peptide related to GnRH or luteinizing
hormone-releasing hormone (LHRH), used to treat metastatic prostate carcinoma.
By inhibiting gonadotropin release upon continuous administration it induces a
hypogonadal state; testosterone levels in the body fall significantly, and this
appears to be the mechanism for suppression of the cancer.
Incorrect Answers Explained
Aminoglutethimide (A) is an aromatase inhibitor mainly used to treat Cushing
disease (it inhibits synthesis of adrenal corticosteroids), and some patients with
metastatic breast carcinoma.
Fludrocorticone (B) is a mineralocorticoid used for chronic adrenal insufficiency
(along with glucocorticoids) or congenital adrenal hypoplasia.
Mifepristone (D) is an abortifacient/oxytocic drug.
Spironolactone (E) is an aldosterone receptor blocker used mainly as for patients
with primary or secondary hyperaldosteronism, and as an adjunct to
management of severe heart failure. Classified as a potassium-sparing diuretic.

Gonadotropins
47
Gonadotropins Luteinizing hormone (LH) and Follicle-stimulating
hormone (FSH)
 Structure
 LH and FSH are glycoproteins found in the anterior pituitary
 LH, FSH, and TSH are all composed of an identical α subunit and a β
subunit unique to each hormone
 Actions and pharmacologic properties
 Activity of LH and FSH is mediated by specific membrane receptors that
cause an increase in intracellular cAMP
 In women, LH
o increases estrogen production in ovary and
o is required for progesterone production by corpus luteum after
ovulation
 FSH required for normal development and maturation of ovarian follicles

Gonadotropins (2)
48
In men, LH
 induces testosterone production by interstitial (Leydig) cells of
testis
 FSH acts on testis to stimulate spermatogenesis and synthesis
of androgen-binding protein
 Therapeutic uses
FSH and LH of pituitary origin are not used pharmacologically
 Rather, menopausal and chorionic gonadotropins (described
below) are used as source of biologically active peptides

49
Gonadotropins (3)
 In females, FSH stimulates ovarian follicle
maturation and estrogen production,
whereas
 LH assists FSH in follicle
development, induces ovulation,
and stimulates corpus luteum to
produce progesterone and
androgens
 In males, FSH stimulates spermatogenesis,
whereas
 LH stimulates Leydig cells in testes to
produce testosterone
The hypothalamic-pituitary–reproduction axis.

Gonadotropins (4)
50
 LH and FSH have analogous but somewhat different
effects in males and females
 Pertinent target cells in male are Leydig and Sertoli
cells of testis, while
 Pertinent target cells in female are thecal and
granulosa cells of ovary
 In each case, a two cell system is coordinated to mediate
sex hormone actions “Two-cell systems for gonadal
hormone action” (The next 2 slides illustrate and explain.)

51
Gonadotropins (5) “Two-cell systems for
gonadal hormone action” Male
 In male, binding of luteinizing hormone (LH) to
the LH receptor (LH-R) activates testosterone
synthesis in Leydig cells
 Testosterone then diffuses into nearby Sertoli
cells, where binding of follicle-stimulating
hormone (FSH) to its receptor (FSH-R) increases
levels of androgen binding protein (ABP)
 ABP stabilizes high concentrations of
testosterone that, together with other FSH-
induced proteins synthesized in Sertoli cells,
promote spermatogenesis in nearby germinal
epithelium (not shown)

52
Gonadotropins (6) “Two-cell systems for
gonadal hormone action” Female
 In female, LH acts in an analogous manner to
promote androgen (androstenedione)
synthesis in thecal cells (Leydig cells equivalent)
 Androgen then diffuses into nearby granulosa
cells, where aromatase converts
androstenedione to estrone, which is then
reduced to the biologically active estrogen,
estradiol
 FSH increases aromatase activity in granulosa
cells, promoting conversion of androgen to
estrogen

53
Le T and Bhushan V. First Aid for the USMLE Step 1 2016 . McGraw-Hill 2016.

54
Klatt EC. Robbins and Cotran Atlas of Pathology, 3rd Ed. Philadelphia: Saunders, 2015.
Normal FM internal genitalia, gross

55Klatt EC. Robbins and Cotran Atlas of Pathology, 3rd Ed. Philadelphia: Saunders, 2015.
Normal FM internal genitalia, radiograph

56Le T and Bhushan V. First Aid for the USMLE Step 1 2016 . McGraw-Hill 2016.
Seminiferous tubules cells, function & location/notes

57
Normal testis, gross

58

59
Hypothalamic-Pituitary-Seminiferous tubules Axis
Le T and Bhushan V. First Aid for the USMLE Step 1 2016 . McGraw-Hill, 2016.

60
Gonadotropins (7)
Human menopausal gonadotropins (menotropins= hMG) and human
chorionic gonadotropin (hCG)
 Menotropins are isolated from urine of postmenopausal women and
contain a mixture of LH and FSH
 Urofollitropin is immunologically purified FSH from urine of
pregnant women
 hCG is produced by placenta and can be isolated and purified from
urine of pregnant women
o hCG is nearly identical in activity to LH
 Recombinant human FSH (follitropin-α and follitropin-β are
available)
o less batch-to-batch variability than preps. derived from urine
 Recombinant LH is also available (Lutropin alpha)

Gonadotropins (8)
61
Menotropins and hCG Therapeutic uses
 Menotropins are used in concert with hCG to stimulate
ovulation in women w functioning ovaries approx. 75% of
women treated w these peptides ovulate
 hCG can be used in both men and women to stimulate gonadal
steroidogenesis in cases of LH insufficiency
 hCG can be used to induce external sexual maturation and
spermatogenesis in men w secondary hypogonadism
o may require months of treatment for effect
 In absence of an anatomic block, hCG can promote descent of
testes in cryptorchidism

Gonadotropins (9)
62
In women with infertility caused by failure to ovulate, hMG and hCG
are used sequentially
 Injection of hMG (or FSH products) over of 5 to 12 days causes
ovarian follicular growth and maturation, and subsequent
injection of hCG ovulation occurs
Adverse effects
 Ovarian enlargement 20% of treated women
 ovarian hyperstimulation syndrome (OHSS) may be life threatening, up to
1% of pts, resulting in acute respiratory distress, ascites, hypovolemia, and
shock
 Multiple births (5-10% of cases)

Question
63
You prescribe bromocriptine for a woman with primary amenorrhea.
Normal menstruation returns about a month after starting therapy.
Which statement best describes the mechanism by which
bromocriptine caused its desired effects.
A. Blocked estrogen receptors, enhanced gonadotropin release
B. Increased follicle-stimulating hormone (FSH) synthesis
C. Inhibited prolactin release
D. Stimulated ovarian estrogen and progestin synthesis
E. Stimulated gonadotropin-releasing hormone (GnRH) release

64
Prolactin Review
 Source Secreted mainly by anterior pituitary
• Structurally homologous to GH
 Function Stimulates milk production in breast, inhibits ovulation in females and
spermatogenesis in males by inhibiting GnRH synthesis and release
• Excessive amounts of prolactin associated with ↓ libido
 Regulation Prolactin secretion from anterior pituitary is tonically inhibited by dopamine
from hypothalamus Prolactin in turn inhibits its own secretion by ↑ dopamine (DA)
synthesis and secretion from hypothalamus
• TRH ↑ prolactin secretion (e.g., in 1° or 2° hypothyroidism)
 Pharm DA agonists (e.g., bromocriptine) inhibit prolactin secretion and can be used in Tx
of prolactinoma
• DA antagonists (e.g., most antipsychotics) and estrogens (e.g., OCPs, pregnancy)
stimulate prolactin secretion

Prolactin Review (2)
65

66
Question
A 40-year-old woman with a history of schizophrenia is receiving treatment with
risperidone, which has resulted in clinical improvement, including lessening of
hallucinations. The patient lives in a group home and her compliance is monitored. She was
brought to the hospital by her attendant with complaints of breast tenderness and no
menstrual period for 3 months. The patient has a history of elevated cholesterol, which has
been lowered in recent months with strict dietary modification, but otherwise has no
chronic health issues. Her BMI (body mass index) is 26 kg/m2, down from 30 kg/m2 six
months ago. Laboratory studies, including thyroid and pregnancy testing, are negative.
Which of the following is the most likely explanation for this patient's amenorrhea?
A. Drug-induced amenorrhea
B. Polycystic ovary syndrome
C. Primary ovarian insufficiency (premature ovarian failure)
D. Schizophrenia
E. Uterine fibroids
F. Weight loss

Answer & Educational Objective
67
A. Drug-induced amenorrhea
Educational Objective:
 The secretion of prolactin is controlled by the inhibitory effect of
hypothalamic dopamine.
 Hyperprolactinemia causes hypogonadism by inhibiting the
release of gonadotrophin-releasing hormone from the
hypothalamus.
 Risperidone and other antipsychotics cause hyperprolactinemia
by their antidopaminergic action.

Control of reproductive
hormones

Gonadal Hormones & Antagonists: Overview
70
 Sex hormones produced by gonads are necessary for
 Conception
 Embryonic maturation and
 Development of primary & secondary sexual characteristics at puberty
 Gonadal hormones are used therapeutically in
 Replacement therapy
 For contraception and
 Management of menopausal symptoms
 Several antagonists are effective in cancer chemotherapy
 All gonadal hormones are synthesized from precursor, cholesterol, in a
series of steps that includes
 shortening of hydrocarbon side chain and
 hydroxylation of steroid nucleus
 Aromatization is last step in estrogen synthesis

Progestins, androgens, and estrogens are steroid
hormones derived from cholesterol
 Major progestins include progesterone and
17α-hydroxyprogesterone
 Androgens include dehydroepiandrosterone
(DHEA), androstenedione, and testosterone
 Estrogens include estrone and estradiol
o Estrogens are aromatized forms of their
conjugate androgens:
• androstenedione is aromatized to estrone
• testosterone is aromatized to estradiol
Synthesis of progestins, androgens & estrogens

Steroid hormone receptors
72
 Steroid hormone receptors (for gonadal steroids and
adrenocortical steroids) are complex proteins inside target cell
 Steroid penetrates cell, binds to receptor and translocates into
cell nucleus principal site of action where RNA synthesis
occurs protein target tissue effect
 Compounds that occupy receptor w/o causing translocation into
nucleus or replenishment of receptors act as antagonists, e.g.
 spironolactone to aldosterone
 cyproterone to androgens
 clomifene to estrogens

A model of interaction of a steroid
Sites and MOA
73
Penetrating cell membrane, hormone
combines with a cytoplasmic receptor
 exposes its DNA binding domain
migrates to nucleus and binds to
specific genes DNA mediated mRNA
synthesis synthesis of functional
proteins
Steroidal hormones include:
 Glucocorticoids
 Mineralocorticoid
 Androgens, Estrogens , Progestins
 Vitamin D & Thyroid Hormone Brunton LL, Chabner BA , Knollmann BC (Eds.). Goodman and Gilman’s
The Pharmacological Basis of Therapeutics. 12th ed. McGraw-Hill, 2011

Estrogens (prototype estradiol)
74
 Estradiol (aka 17β-estradiol) is most potent estrogen produced & secreted by
ovaries
 It is principal estrogen in premenopausal women
 Estrone, a metabolite of estradiol, has approximately one-third estrogenic
potency of estradiol
 Estrone is primary circulating estrogen after menopause generated
mainly from conversion of androstenedione in peripheral tissues
 Estriol another metabolite of estradiol significantly less potent than is
estradiol
 present in significant amounts during pregnancy, b/c it is principal estrogen
produced by placenta
 Synthetic estrogens, such as ethinyl estradiol undergo less first-pass
metabolism than do naturally occurring steroids and, thus, are effective when
administered orally at lower doses

Estrogen (2) Capsule
75
 Source Ovary (17β-estradiol), placenta (estriol), adipose tissue
(estrone via aromatization)
 Potency: estradiol > estrone > estriol
 Function
 Development of genitalia & breast, FM fat distribution
 Growth of follicle, endometrial proliferation, ↑myometrial
excitability
 Upregulation of estrogen, LH, and progesterone receptors
 Feedback inhibition of FSH and LH, then LH surge
 Stimulation of prolactin secretion
 ↑ transport proteins, ↑SHBG
 ↑HDL and ↓ LDL
All estrogens are derived from aromatization of precursor androgens

Estrogens (3)
76
Estradiol
Estrone
Ethinyl Estradiol
Johannsen EC & Sabatine MS. PharmCards: Review Cards
for Medical Students, 4th Ed. LLW, 2010.
Estrogen Synthesis

Estrogens (4)
77
Mechanism:
 Bind to estrogen receptors (ERα and ERβ) & are transported into nucleus 
receptor–hormone complex binds to specific sequences of nucleotides
(estrogen response elements) →↑transcription of certain genes
 Estrogen receptors found in FM reproductive tract, breast, pituitary, and
hypothalamus
 Exogenous estrogens inhibit endogenous FSH secretion suppress ovulation
Clinical Use:
 Oral contraceptives (with a progestin): inhibits ovulation, dysmenorrhea,
polycystic ovarian disease (PCOD), primary hypogonadism
 Used for postmenopausal hormone replacement therapy to ↓ signs and
symptoms caused by loss of ovarian function (vasomotor symptoms or “hot
flashes,” genital atrophy, dryness etc.) and
 ↓ bone loss and fractures fallen out of favor b/c of cardiovascular adverse
effects (more on this to follow)

Estrogens (5)
78
Adverse Effects:
 Postmenopausal uterine bleeding, hypertension, migraines, cholestasis,
hepatic adenomas
 Estrogen-containing OCs increase risk of episodes of migraine headache
 Endometrial hyperplasia, ↑ risk of endometrial cancer (if given w/o
progestin) ↑ risk of breast cancer (if given w/ progestin)
 ↑ thromboembolic events, both arterial (MI, stroke) and venous (DVT, PE)
Of note:
 Commercial estrogens include Estradiol, Estrone (Premarin), and Ethinyl
Estradiol (Estinyl =most common estrogen in COCs)
 OCs are available in many estrogen plus progestin combinations
 Diethylstilbestrol (DES), a semisynthetic estrogen previously used during
first trimester of pregnancy, was assoc. w infertility & ↑ incidence of
vaginal & cervical clear cell adenocarcinomas in female offspring

Clomiphene (Clomid) Antiestrogen (SERM)
79
Mechanism: Antiestrogens interfere w binding of estrogen w its specific receptor,
and also alter conformation of estrogen receptor such that it fails to activate
target genes
 Binds to estrogen receptors (ERs) and competitively blocks binding of
endogenous estrogens
 acts as an antagonist in hypothalamus and as a weak agonist in ovaries
and endometrium
 Thus, has also been classified as SERM by some
o Fulvestrant, by contrast, is a pure estrogen antagonist (all tissues)
 In premenopausal women: blockade at ER in anterior pituitary and
hypothalamus → disrupt feedback inhibition to GnRH, FSH/LH secretion
→↑secretion of GnRH, FSH/LH →↑gametogenesis & steroidogenesis in
ovaries
 In postmenopausal women: little to no effect

Clomiphene (2)
80
Clinical Use:
 Treatment of female infertility (anovulation)
 Treatment of male infertility (oligozoospermia): success variable
Adverse Effects:
 Multiple births
 Excessive enlargement of ovaries and ovarian cysts (caused by ↑ FSH and
LH and a direct effect of clomiphene)
 Hyperstimulation syndrome: although multiple ovulation is common, in
some patients, this is accompanied by an intense hypersensitivity
(anaphylactoid) response
Of note: fulvestrant (pure antiestrogen) may be indicated in Tx of ER-positive
breast cancer resistant to tamoxifen

Tamoxifen (Nolvadex) SERM
81
Mechanism: A selective estrogen receptor modulator (SERM), exhibits tissue-
specific pro-estrogenic and anti-estrogenic effects
 Binds to estrogen receptors (ERs) and competitively blocks binding of
endogenous estrogens tamoxifen– ER complex alters estrogen-responsive
gene expression
 Tamoxifen acts as an antagonist within breast (inhibiting cellular
proliferation) and as an agonist within bone (exerting an antiresorptive
effect) and uterus (inducing cellular proliferation)
 b/c it is an agonist in uterus associated w increased risk of endometrial
hyperplasia and cancer
Clinical Use: Endocrine treatment of both early and metastatic ER-positive
breast cancer in both pre- and postmenopausal women
 May be useful in chemoprevention of breast cancer in women at high risk
 Reduces severity of osteoporosis (but not used for this indication b/c of
availability of agents w superior side effect profiles)

Tamoxifen (2)
82
Adverse Effects:
 Hot flashes, menstrual irregularities, vaginal bleeding and discharge,
nausea, vomiting
 ↑ risk of endometrial cancer
 Venous thromboembolic events (DVT, PE)
Of note:
 toremifene SERM with tissue specificities similar to tamoxifen
 raloxifene SERM that is an antagonist in breast and uterus and an agonist
in bone
o It is used to treat postmenopausal osteoporosis
o Not associated w ↑ risk of endometrial cancer but is assoc. w DVT
and PE (albeit, less than tamoxifen)
 NB: Compared w tamoxifen, raloxifene is as effective in preventing
invasive breast cancer (although less effective in preventing carcinoma in situ)
and is less likely to cause endometrial cancer or DVT/PE

Selective Estrogen Receptor Modulators
84
 SERMs are hormone-like drugs with tissue-selective estrogenic activities
 Act as competitive antagonists or weak agonists:
 estrogenic in bone but no effect or antagonistic in breast and
endometrium
 Tamoxifen, first classed as antiestrogenic is used to prevent and treat
hormone-responsive breast cancer inhibits cell proliferation and reduces
tumors as a result of estrogen receptor antagonism
 It has estrogenic actions in uterus  stimulates endometrial
proliferation and thickening increases carcinoma risk and
 In skeletal reduces bone loss
 In cardiovascular systems improves lipid profiles
Adverse effects
 Hot flashes, menstrual abnormalities, thrombosis, and pulmonary
embolism

SERMs (2)
85
 Raloxifene is used to prevent and treat osteoporosis:
 Estrogen agonist action in bone and on lipid metabolism
 Estrogen antagonist action in breast and uterus
o it is antiproliferative for estrogen positive breast cancer
cells
o lowers risk of breast cancer in high-risk women
o does not result in ↑ incidence of endometrial cancer (such
as estrogen and tamoxifen do)
o lowers LDL cholesterol
Adverse effects
 hot flashes, leg cramps, and venous thromboembolism

SERMs
86Raff RB, Rawls SM, Beyzarov EP. Netter's Illustrated Pharmacology, Updated Edition. Philadelphia: Sanders, 2014

Antiestrogens
87
Antiestrogens are distinguished from SERMs in that they act as pure
antagonists in all tissues
 Fulvestrant, for example, is a pure estrogen antagonist (all tissues)
The antiestrogen clomiphene binds competitively to estrogen receptors and
decreases sites available to endogenous estrogen including hypothalamic
and pituitary estrogen receptors
 This inhibition leads to a disruption in negative feedback of estrogens on
hypothalamus and pituitary a subsequent ↑ in secretion of GnRH and
gonadotropins, and ultimately stimulation of ovulation
 Used to treat infertility associated with anovulatory menstrual cycles but it
is effective only in women with a functional hypothalamus and adequate
endogenous estrogen production
Adverse effects clomiphene are dose related , include ovarian enlargement,
vasomotor symptoms, visual disturbances and (multi-birth pregnancy )

Clomiphene
MoA Illust.
Clomiphene acts by inhibiting
negative feedback effects of
estrogen at hypothalamic-pituitary
levels, increasing follicular-
stimulating hormone (FSH)
concentrations and thereby
enhancing follicular maturation
Remember
clomiphene is a weak agonist in
ovaries & endometrium Thus,
has also been classified as SERM by
some

Anastrozole (Arimidex) aromatase inhibitor
89
Mechanism: Competitive inhibitor of aromatase final enzyme complex in
synthesis of estradiol and estrone from androgens androstenedione and
testosterone, respectively
Clinical Use: Used in postmenopausal women with an ER−positive breast cancer
when tamoxifen is contraindicated or has proven ineffective
 In some clinical trials, efficacy shown to be superior to SERMs
 in premenopausal women, normal ovarian function leads to a
counterproductive feedback loop: ↓ estrogens → compensatory ↑
gonadotropins → ↑ ovarian androgen synthesis and aromatase expression
→↑estrogen
Adverse Effects: Arthralgias, myalgias, ↓ bone mineral density w ↑ risk of
osteoporosis (mediated by blocking beneficial estrogen effects on bone)
NB: Unlike tamoxifen, no endometrial cancer or thromboembolic events

Anastrozole (2)
90
Johannsen EC & Sabatine MS. PharmCards: Review Cards for Medical Students, 4th Ed. LLW, 2010.
Estrogens estradiol and estrone from
Androgens androstenedione and testosterone

Aromatase inhibitors (3)
91
Of note:
 letrozole and exemestane are other aromatase inhibitors, w latter
being an irreversible inhibitor
 Utility of aromatase inhibitors for chemoprevention of breast cancer is
under study
Aminoglutethimide was first clinically used aromatase inhibitor
 It also blocks cholesterol → pregnenolone, first step in adrenal steroid
synthesis
 Used to treat prostate cancer, breast cancer, Cushing’s syndrome, and
adrenal tumors has fallen out of favor b/c of its nonselectivity

Progesterone
92
 Progesterone, the natural progestogen, is produced in response
to luteinizing hormone (LH) by both
 females (secreted by corpus luteum during second half of
menstrual cycle, and by placenta) and by
 males (secreted by testes)
 It is also synthesized by adrenal cortex in both sexes
 Progestins (=synthetic progestogens) generally exert
antiproliferative effects on female endometrium by promoting
endometrial lining to secrete rather than proliferate

Progestogens Mechanism of Action
93
Progestogens exert their MOA in a manner analogous to other
steroid hormones (activation of SRE→↑genes transcription)
 In females promotes development of a secretory endometrium
that can accommodate implantation of a newly forming embryo
high levels of progesterone released during second half of
menstrual cycle (luteal phase) inhibit production of
gonadotropin prevent further ovulation
 If conception takes place progesterone continues to be secreted,
maintaining endometrium in a favorable state for continuation of
pregnancy and reducing uterine contractions
 If conception does not take place release of progesterone from corpus
luteum ceases abruptly decline stimulates onset of menstruation

Progestins (synthetic progestogens)
94
Mechanism of Action:
 Regulate transcription: bind to progestin receptor
→activation of steroid response elements
→↑transcription of certain genes RNA synthesis
protein synthesis target tissue effect
 Progesterone (major naturally occurring progestin in
humans) causes
o development of secretory tissue in breast
o maturation of uterine endometrium, and
o can inhibit GnRH, FSH, and LH secretion

95
Progestins (2)
Clinical Use:
 Contraception
 Prevent ovulation by inhibiting midcycle LH/FSH surge
 Create suboptimal endometrial environment for implantation
 Makes cervical mucus “hostile” to sperm disrupt uterine & tubal motility
 Given with estrogens as part of postmenopausal hormone replacement
therapy to ↓ endometrial hyperplasia and risk of endometrial cancer
 Dysfunctional uterine bleeding (DUB, usually due to continuous estrogen
production w/o progesterone)
 Endometriosis: progestins can prevent proliferation of ectopic endometrial tissue
 Bleeding Fibroid Tumors: Progestins (medroxyprogesterone) can partially suppress
estrogen stimulation  in turn can decrease fibroid growth and vaginal bleeding
 Withdrawal bleeding: a diagnostic test used to evaluate amenorrhea
 Menstruation after cessation of progestin therapy suggests uterus has been
primed by endogenous estrogens

Progestins (3)
96
Adverse Effects:
 Hypertension* (but less so than estrogen)
 May ↓ HDL
 Weight gain
 hypermenorrhea
N.B. *Drospirenone =only progestin drug with antihypertensive
properties. Structurally related to spironolactone and acts as an
aldosterone receptor antagonist. Therefore, it causes an increased
renal sodium excretion, which can account for its diuretic and
antihypertensive effects.

Androgens (Prototype testosterone)
97
 Androgens are a group of steroids that have anabolic and/or masculinizing
effects in both M and FM
 Testosterone, most important androgen in humans, is synthesized by
 Leydig cells in testes
 thecal cells in ovaries (smaller amounts) and
 adrenal gland in both sexes
 Other androgens secreted by testes are 5α-dihydrotestosterone (DHT),
androstenedione, and dehydroepiandrosterone (DHEA) in small amounts
 In adult males, testosterone secretion by Leydig cells is controlled by GnRH
from hypothalamus stimulates anterior pituitary gland to secrete FSH and
LH
N.B. Testosterone is essentially a prohormone only
modest affinity for androgen receptor. Test. is converted in
target tissues to more active DHT (dihydrotestosterone)
which binds to androgen receptor with an affinity ten
times higher than that of testosterone.

98
Pathway of synthesis of testosterone in the Leydig cells of the testes
 In Leydig cells, 11 and 21
hydroxylases (present in
adrenal cortex) are absent
but CYP17 (17 α-
hydroxylase) is present
thus androgens &
estrogens are synthesized/
but corticosterone &
cortisol are not formed
Bold arrows indicate favored pathways.
Brunton LL, Chabner BA , Knollmann BC (Eds.). Goodman and Gilman’s
The Pharmacological Basis of Therapeutics. 12th ed. McGraw-Hill, 2011

Direct effects of testosterone and effects mediated
indirectly via DHT or estradiol
Brunton LL, Chabner BA , Knollmann BC (Eds.).
Goodman and Gilman’s The Pharmacological
Basis of Therapeutics. 12th ed. McGraw-Hill, 2011

Androgens (3)
100
Mechanism: Binds to cytosolic receptor  taken into nucleus activates
transcription of testosterone responsive genes
 In skin, prostate, seminal vesicles, and epididymis, testosterone is
converted by 5-α reductase to more potent dihydrotestosterone
Physiologic effects: ↑overall body growth (↑ protein synthesis and ↓ protein
breakdown), penile and scrotal growth, development of secondary sex
characteristics
↑ RBC production: secondary to both ↑ erythropoietin production by kidney and
direct stimulation of Epo-sensitive elements in bone marrow
 Also, ↑ erythrocyte 2,3-DPG levels hence ↑ availability of oxygen
Clinical Use:
 Replacement therapy in hypogonadism
 Anabolic agent (frequently abused)
Primary testicular failure such as result of
bilateral anorchia, Klinefelter’s (XXY)
karyotype, surgery, chemotherapy and
radiotherapy, or secondary testicular failure
as a result of hypothalamic– pituitary disease.

Androgens (4)
101
Adverse Effects:
 Men: acne, gynecomastia, testicular atrophy caused by suppression of
gonadotropins, azoospermia, prostatic hypertrophy, physical aggression
 Women: masculinization
 Cholestatic jaundice, ↑ transaminases, hepatocellular carcinoma
o 17α-alkylated androgens are only androgens that cause
hepatotoxicity
Of note:
 methyltestosterone (android) and fluoxymesterone are similar agents
 oxandrolone and nandrolone are anabolic steroids that are structurally
similar to testosterone and act as androgen receptor agonists
o can facilitate weight gain
o prior to development of recombinant erythropoietin, were used to treat
anemia of chronic kidney disease

102
Androgens (5)
 Dehydroepiandrosterone (DHEA) and its
sulfate (DHEAS) and androstenedione are
adrenal steroids that are androgen
precursors
 DHEA and DHEAS have been marketed as
dietary supplements to improve strength,
well-being, cognition & libido (little data to
support these claims)  have been abused
by professional athletes as an alternative to
anabolic steroids
 Androstenedione was a dietary supplement
used, most notably, by Major League Baseball
players as a performance enhancing drug it
has since been banned
Johannsen EC & Sabatine MS. PharmCards: Review
Cards for Medical Students, 4th Ed. LLW, 2010.

Flutamide (Eulexin) Anti-androgen
103
Mechanism: An anti-androgen, competitive antagonist at androgen receptor
 Prostate growth depends on androgens so androgen deprivation ↓
progression of prostate cancer
o Flutamide does not affect testosterone production by Leydig cells
Clinical Use: Androgen deprivation therapy in prostate cancer, both for locally
advanced disease (in conjunction w radiation therapy or surgery →↑survival) and
for metastatic disease (alleviate bone pain; modest survival benefit)
 It is used combination with GnRH agonists (e.g., leuprolide)
o N.B. has limited efficacy when used alone b/c it ↑ LH secretion that
stimulates higher serum testosterone concentrations
Side Effects: Gynecomastia, Hepatitis
Of note: bicalutamide and nilutamide are similar androgen receptor blockers
 cyproterone is an anti-androgen w progestogenic effects that is used in
women to ↓ hirsutism and in men to ↓ sexual drive (hypersexuality)

Flutamide (2)
104

Finasteride (Proscar) Anti-androgen
105
Mechanism: 5α-reductase inhibitor that blocks conversion of testosterone to
more potent dihydrotestosterone (DHT)
 DHT is the principal androgen that acts on prostate
Clinical Use:
Benign prostatic hyperplasia (BPH): ↓ prostate size and hence obstructive
symptoms of BPH such as difficulty in initiating voiding, ↓ caliber and force of
urinary stream, sensation of incomplete emptying, and frequent urination
 May take 6–12 months to have a noticeable effect
Androgenetic alopecia (male pattern baldness)
Adverse Effects: Loss of libido, erectile dysfunction
Contraindication: teratogenic & can be absorbed through skin women who
may be pregnant should not take or handle crushed or broken tablets

Finasteride (2)
106

Finasteride (3)
107
Of note: dutasteride is a related inhibitor of 5α-reductase used for
male androgenetic alopecia and BPH
 Utility of 5α-reductase inhibitors in prevention of prostate cancer
remains controversial
o ↓ overall incidence of prostate cancer but ↑ risk that
tumors that do develop are high grade
o no effect on mortality
 α-blockers are also used to treat BPH (e.g., prazosin)

Question
108
A 66-year-old Caucasian male is treated with flutamide for
metastatic prostatic cancer. He experiences significant relief of his
bone pain soon after initiation of the therapy. The primary tumor
decreases in size. Which of the following is the best explanation
for the changes observed in this patient?
A. Decreased Leydig cell stimulation
B. Decreased Leydig cell androgen synthesis
C. Decreased peripheral androgen aromatization
D. Decreased peripheral androgen conversion
E. Impaired ligand-receptor Interaction

Answer & Educational Objective
109
E. Impaired ligand-receptor Interaction
Educational Objective:
Flutamide is a non-steroid anti-androgen that competes with
testosterone and DHT for testosterone receptors
It is used for treatment of prostate cancer in combination with
GnRH agonists

110
 (Choice A) Gonadotropin-releasing hormone (GnRH) agonists
(leuprolide, goserelin, nafarelin and histrelin) bind to GnRH receptors
in anterior pituitary and inhibit synthesis of LH and FSH, if
administered continuously
o Decreased amount of LH leads to decreased Leydig cell
stimulation and diminished testosterone synthesis
 (Choice B) Ketoconazole is a weak antiandrogen that decreases
synthesis of steroid hormones in gonads and adrenals
 (Choice C) Decreased peripheral androgen aromatization refers to
mechanism of anastrozole, a nonsteroidal aromatase inhibitor which
blocks estrogen production selectively
o Anastrozole is an effective treatment for postmenopausal women
with breast cancer in whom the greatest source of estrogen is the
conversion of androstenedione, produced in adrenal glands, to
estrone in liver, muscle, and fat, through aromatization
 (Choice D) Finasteride decreases peripheral conversion of testosterone
into dihydrotestosterone by inhibiting the 5-α-reductase
o It is used for treatment of BPH and male baldness
Incorrect Answers Explained
Endocrine Pharm. UWorld, 2014.

Combination Oral Contraceptives (COCs)
112
 COCs contain both estrogen and progestin and prevent
pregnancy through two main mechanisms
1. They inhibit ovulation (most important ) via a negative
feedback mechanism on hypothalamus which alters normal
pattern of FSH and LH secretion by anterior pituitary
o Estrogen suppresses FSH release from pituitary during
follicular phase of menstrual cycle and inhibits midcycle
surge of gonadotropins
o Progestin inhibits estrogen-induced LH surge
2. thicken cervical mucus, thus providing a physical barrier that
slows or stops sperm motility (progestin component)

COCs (2)
113
 COCs also produce alterations in genital tract
 Progestin responsible for changing cervical mucus and
rendering it unfavorable for sperm penetration even if
ovulation occurs
 COCs induce an environment in endometrium that is
unfavorable for implantation
 COCs may also alter tubal transport of sperm, egg, and
fertilized ovum through fallopian tubes

COCs (3)
114
Raff RB, Rawls SM, Beyzarov EP. Netter's Illustrated Pharmacology, Updated
Edition. Philadelphia: Sanders, 2014

Major Adverse Effects of COCs
115
 Major effects, of excess or lack of estrogen or progestin, include
 breast fullness
 depression
 dizziness
 edema
 migraine and cluster headaches, and
 vomiting
 Serum lipoprotein profiles can change:
 estrogen increases HDL levels and decreases LDL levels
 progestins (esp. norgestrel) cause unwanted opposite effect
o decreases HDL levels and increases LDL levels

Major Adverse Effects of COCs (2)
116
 COCs are associated with
 gallbladder disease
 cholestasis
 abnormal glucose tolerance
 hypertension and thromboembolic disorders (estrogen
component)
 COCs are contraindicated if pt. has
 cerebrovascular and thromboembolic disease
 estrogen-dependent neoplasms
 abnormal genital bleeding
 chronic diabetes, or
 liver disease

Adverse Effects
of COCs (3)
117
Raff RB, Rawls SM, Beyzarov EP. Netter's Illustrated Pharmacology,
Updated Edition. Philadelphia: Sanders, 2014

Benefits COCs
118
 Benefits include
reduced risk of
 ovarian cysts
 benign breast disease, and
 ectopic pregnancy
improved
 premenstrual symptoms
 dysmenorrhea
 endometriosis
 acne and hirsutism
 COCs reduce endometrial and ovarian tumor incidence
 their cause of other neoplasms is controversial

COCs Drug-Drug Interactions
119
 Cytochrome P-450 enzyme inducers (e.g. chronic alcohol use
phenytoin, phenobarbital, rifampin, carbamazepine) enhance hepatic
metabolism of oral contraceptives (especially estrogen component) leading
to reduced contraceptive levels and unintended pregnancy (contraceptive
failure)
 P-450 enzyme inducers also interacts by inducing synthesis of hormone-
binding globulins more hormone molecules are bound to protein, and so
less free (active) drug is in circulation
 Some antibiotics (e.g., tetracyclines) interact w OCs
 mechanism: antibiotics suppress gut flora that participate in
enterohepatic recycling of OCs When bacteria are suppressed OCs
secreted into gut are lost in feces, rather than being reabsorbed

120
Skill Keeper: Cytochrome P450 & Hormonal Contraceptives
 Hormonal contraceptives usually contain lowest doses of estrogen and
progestin components that prevent pregnancy
 Margin between effective and ineffective serum concentrations of steroids is
narrow which presents a risk of breakthrough bleeding and also unintended
pregnancy resulting from drug–drug interactions
 Most steroidal contraceptives are metabolized by cytochrome P450 isozymes
1. How many drugs can you identify that decrease the efficacy of hormonal contraceptives
by increasing their metabolism?
2. When one of these drugs is prescribed for a woman who already is using a combined
hormonal contraceptive, what should be done to prevent pregnancy?

121
Skill Keeper Answers: CYP P450 and Hormonal Contraceptives
1. Gonadal steroids and their derivatives are metabolized primarily by cytochrome P450
3A4 (CYP3A4) family of enzymes
 Inducers of CYP3A4 include barbiturates, carbamazepine, corticosteroids, griseofulvin,
phenytoin, pioglitazone, rifampin, and rifabutin.
 potential reduction in contraceptive efficacy of OCs by carbamazepine and phenytoin
are of particular importance because these drugs are known teratogens
 St. John’s wort, an unregulated herbal product, contains an ingredient that induces
CYP3A4 enzymes and can reduce the efficacy of hormonal contraceptives.
2. To prevent an unwanted pregnancy, it would be advisable to use a COC pill with a higher
dose of estrogen (e.g., a formulation containing 50 mcg of ethinyl estradiol).
 Alternatively, or additionally, women may use a barrier form of contraception or
switch to an IUD.

Estrogen and Coagulation
122
 Estrogens may affect fibrinolytic pathways and cause
 ↑ in coagulation factors II, VII, VIII, IX, X, and XII (the main action) and
 ↓ in anticoagulation factors
o protein C
o protein S
o plasminogen activator inhibitor protein I
o antithrombin III
By causing imbalance between coagulation and anticoagulation, estrogens
may produce serious associated complications, including
 thromboembolism
 thrombophlebitis
 myocardial infarction, and
 cerebral and coronary thrombosis
 These complications are more likely to occur in women who
smoke and are older than 35 years
N.B. These actions augment risk of
thromboembolic disease in women
taking COCs about threefold compared
to women taking no hormones.

Estrogen and Coagulation (2)

Estrogen and Coagulation (3)
124

Progestin-Only Contraceptives
125
Progestin thickens cervical mucus (decreases sperm penetration)
and alters endometrium thus preventing implantation
Progestin-only formulations are available as pills (“minipills”),
depot injections, and implants
 Pills contain norethindrone or norgestrel, taken daily on a
continuous schedule
o less effective than COCs b/c they block ovulation in only 60% to 80% of
cycles
Absence of estrogen also lowers risk of thromboembolic
disorders a major advantage, especially, for women who smoke

Progestin-Only Contraceptives (2)
126
 Depot injections of medroxyprogesterone acetate (MPA) impair
implantation and produce plasma drug levels high enough to
prevent ovulation in virtually all pts by slowing GnRH release
thus prevents LH surge required for ovulation
 Progestin implants (subdermal capsules containing levonorgestrel)
offer contraception for approximately 5 years
 Nearly as effective as sterilization, w completely reversible effects if
implants are surgically removed
 Note: Levonorgestrel is also an effective postcoital contraceptive
 Adverse effects
o ↑ appetite & weight gain
o breast tenderness
o headaches, and
o frequent occurrence of irregular menstrual bleeding

Progestin-Only Contraceptives (3)

Morning After Pill (Emergency contraception)
128
Postcoital (or emergency) contraceptives consist of
 high-dose estrogen (ethinyl estradiol), administered within 72 hours of
coitus and continued twice daily for 5 days
 Alternatively, 2 doses of ethinyl estradiol plus norgestrel can be used
within 72 hours of coitus- followed by another 2 doses 12 hrs. later
 An alternative emergency contraceptive is progesterone
agonist/antagonist ulipristal  indicated for contraception within 4-5
days of unprotected intercourse
Emergency contraception does not interrupt an established
pregnancy, which officially begins w implantation
Emergency contraceptives are associated w a high incidence of
N/V b/c of high doses of hormones used

Emergency contraception(2)
129
Both ethinyl estradiol and norgestrel may
 inhibit or delay ovulation if taken during first half of cycle
 alter endometrial receptivity for implantation
 interfere w Fx of corpus luteum that maintains pregnancy
 decrease sperm penetration
 affect fertilization, and
 alter transport of sperm, egg, or embryo

Morning After Pill (3)

“The Abortion Pill” [Mifepristone (RU-486)]
131
 Mifepristone (RU-486) a progestin antagonist w partial agonist
activity (an abortifacient/oxytocic drug)
Use
 Medical termination of intrauterine pregnancy through 49 days
gestation
MOA
 Taken early in pregnancy, mifepristone interferes w progesterone
causing a decline in human chorionic gonadotropin (hCG) and
subsequent abortion of fetus
 Mifepristone also sensitizes endometrium to prostaglandins
terminate gestation by inducing uterine contractions
o Therefore, it is rational to use mifepristone w prostaglandin
misoprostol (PGE1 analog), esp. b/c mifepristone alone is more likely
to cause an incomplete abortion

Mifepristone (2)
132
Raff RB, Rawls SM, Beyzarov EP. Netter's Illustrated Pharmacology,
Updated Edition. Philadelphia: Sanders, 2014
Dosing
Regimen consists of a single dose
of mifepristone, followed by a
single dose of misoprostol 2 days
later
Adverse Effects
 Expected major adverse effects
are cramping and bleeding,
which are similar to symptoms
of a spontaneous abortion
 Incomplete abortion is also
possible

COCs and Progestins
134
 COCs and progestins also suppress LH and FSH so they
render endometrial tissue thin and compact thus alleviating
endometriosis
 COCs can be taken continuously or cyclically
 Therapy can be stopped after 6 to 12 months or continued
indefinitely
 Progestins may have greater adverse effects than COCs
 a depot form may delay return to fertility

COCs and Progestins (2)
135
 Combination oral contraceptives (COCs) are effective in blocking
ovulation in approximately 98% of patients and come in many
different formulations
 Ethinyl estradiol and mestranol are commonly used estrogens
 Desogestrel and Norgestimate are commonly used progestins
 Also used for contraception are progestin-only formulations to
inhibit or delay ovulation
 Emergency preparations such as mifepristone (RU-486), given
along with misoprostol, for medical termination of intrauterine
pregnancy

136
 Although COCs do have adverse effects, they are associated with
benefits unrelated to contraception, such as
 a reduced risk of ovarian cysts, and
 can ameliorate menstrual and reproductive system abnormalities
 acne, and hirsutism
 COCs ability to induce neoplasms is controversial
 Doses of estrogen used in hormone replacement therapy (HRT)
for treatment of postmenopausal symptoms including
 vasomotor manifestations
 genitourinary atrophy, and
 osteoporosis
are substantially less than those used in oral contraceptives (OCs)

137
Contraindications to COCs
 Combination (estrogen/progestin) contraceptives are
contraindicated in women with a history of:
 thromboembolic disease
 cerebrovascular disease
 migraine headaches with aura
 estrogen-dependent cancer
 impaired hepatic function or active liver disease,
undiagnosed uterine bleeding, and
 suspected pregnancy

Endometriosis
(ectopic growth of endometrium)
139
 Endometriosis is characterized by presence of endometrial tissue
 on ovaries, fallopian tubes, and peritoneum or
 on more remote extrauterine sites such as bowel, rectum,
kidneys, and lungs
 Most frequent symptoms of genital tract endometriosis include:
 dyspareunia
 dysmenorrhea
 low back pain
 menstrual irregularities, and
 infertility

Endometriosis (2)
140
Pathogenesis
 endometriosis is multifactorial essentially it involves
retrograde menstruation
 endometrial cells implant in pelvis and create “endometrial
islands” that bleed and cause local inflammation in response
to cyclic hormonal stimulation
Natural History
 Endometriosis is likely to remain problematic as long as
menstruation continues
 Therefore, mainstay of medical therapy involves interrupting
or decreasing menstruation

141
Endometriosis (3) Pelvis: Sites of Implantation
Klatt EC. Robbins and Cotran Atlas of Pathology, 3rd Ed.
Philadelphia: Saunders, 2015.

Endometriosis (4)
142
Laparoscopic Views

Endometriosis Treatment (Danazol)
143
Danazol is a synthetic androgen w antiprogestin activity that
suppresses ovarian estrogen production by inhibiting midcycle
surge of LH / FSH from pituitary
 Resultant relatively hypoestrogenic state leads to atrophy of ectopic
endometrial lesions and pain relief
 Danazol is started when patient is menstruating and is continued for 6 to 9
months, depending on disease severity
 During therapy, pt. is usually amenorrheic, but ovulation may still occur
 Patients should use nonhormonal contraception b/c use of danazol
during pregnancy should be avoided (Risk Categories for Use of Drugs in
Pregnancy= FDA Category X)

Endometriosis Treatment (2)
144
Adverse effects
 characteristic of estrogen deficiency, include
 headache
 flushing
 sweating
 atrophic vaginitis
 Androgenic side effects include
 acne
 edema
 hirsutism
 deepening of voice
 weight gain
N.B. Although danazol highly effective in relieving
symptoms of endometriosis, newer, better-
tolerated treatments have reduced its use.

146

Estrogen Decline
148
In premenopausal period, ovarian secretion of estradiol (E2) (most potent form
of estrogen) is major source of estrogen production
In menopause, production of estradiol diminishes as ovaries cease to function
 In postmenopausal period (1 year after amenorrhea) gonadotropin levels
increase and ovarian hormone levels decrease secondary to ovarian failure
Peripheral conversion of adrenal androstenedione to estrone (E1) (one third
potency of estradiol) becomes principal source of estrogen
 Consequences of this estrogen (ovarian estradiol) deficiency include
 vasomotor symptoms
 genitourinary atrophy
 osteoporosis
N.B. Menopause assoc. symptoms include hot flashes,
vaginal atrophy, osteoporosis, and coronary artery disease
(Remember, menopause causes HAVOC: Hot flashes,
Atrophy of Vagina, Osteoporosis, and Coronary artery
disease)

Pituitary & Ovarian Hormone Changes in Menopause
 Hormone levels ↑ and ↓ cyclically during menstrual cycle
 Modulation occurs by pulsatile release of gonadotropins
and positive and negative feedback loops
 In postmenopausal period, FSH &L H levels ↑ and ovarian
hormone levels ↓ secondary to ovarian failure
 Endogenous estrogen is primarily of adrenal origin, and E1 to
E2 ratio is reversed
RaffRB,RawlsSM,BeyzarovEP.Netter'sIllustrated
Pharmacology,UpdatedEdition.Philadelphia:Sanders,2014

Vasomotor Symptoms
150
 Chief vasomotor symptoms reported by women are described as hot
flashes occur over anterior part of body, especially face, neck, and chest
 Usually lasting a few minutes but varying in frequency and severity
 Symptoms are caused by a decrease in tone of arterioles results in
increased blood flow to skin subsequent increase in skin temperature
 Hot flashes seem to be synchronous w increased hypothalamic release of
GnRH that occurs in response to estrogen deficiency
 GnRH neurons are coincidentally close to hypothalamic centers that regulate temperature
 Estrogen replacement therapy re-establishes feedback control of
hypothalamic secretion of GnRH leading to a decreased incidence of hot
flashes

Hot flashes

Genitourinary Atrophy
152
 Postmenopausal estrogen deficiency leads to changes in vagina, including
 thinning of epithelium
 a ↓ blood supply
 dryness, and
 a change from acidic to a neutral or alkaline pH  predisposes to infection
 Chief symptoms include
 vaginal discharge secondary to infection and
 painful intercourse from dryness
 dysuria and urinary incontinence from bladder atrophy
 Estrogen Tx
 ↑ vascularity and epithelial proliferation of vagina
 allows greater lubrication
 ↑protection from vaginitis & reduced vaginal trauma from intercourse
 reverses atrophy of bladder

Osteoporosis and Estrogen
153
 Lower estrogen levels enhance calcium efflux from bone mineral
stores  ↑ serum Ca2+ levels
 These effects suppress PTH secretion reduces vitamin D3
synthesis ↓ intestinal calcium absorption
 Estrogen deficiency and advanced age also reduce secretion of
hormone calcitonin inhibits bone resorption
 Bones thin and weaken, w ↑ risk of fractures, especially
compression fractures of vertebrae (and thus height loss) and
minimal-trauma hip and wrist fractures

Osteoporosis and Estrogen (2)
154
Preventive and therapeutic measures include use of estrogen,
calcium, vitamin D, calcitonin, fluoride, bisphosphonates, and drugs
such as raloxifene
Therapeutic estrogen primarily
 ↓ bone resorption reduces bone loss (does not restore bone mass)
 ↓ calcium excretion, producing a premenopausal calcium balance
 ↑ vitamin D3 synthesis
 ↑serum calcitonin levels, and
 (given with calcium) decreases hip fracture occurrence
N.B. In the WHI Trial treatment of postmenopausal women with conjugated
estrogen plus medroxyprogesterone (in women with a uterus) or with
conjugated estrogen alone (in women without a uterus), there was improved
bone density and a decreased risk of bone fractures

Marc Imhotep Cray, MD 155Raff RB, Rawls SM, Beyzarov EP. Netter's Illustrated Pharmacology, Updated Edition. Philadelphia: Sanders, 2014

Role of Progestins in Hormone Replacement
Therapy (HRT)
156
 Unopposed estrogen is associated w a large ↑ in incidence of endometrial
carcinoma is thought to be due to hormone’s continuous stimulation of
endometrial hyperplasia
 In pts. w an intact uterus, progestin is added to estrogen therapy b/c it
reduces endometrial hyperplasia by
 ↑ local conversion of estradiol to the less potent estrone
 converting endometrium from a proliferative to a secretory state, or
 both
 Progestin also reduces risk of estrogen-induced irregular bleeding
 Pts. who have undergone a hysterectomy can use unopposed estrogen
therapy progestin is unnecessary, especially b/c it may unfavorably alter
HDL/LDL ratio

158
Route of Hormone Administration
 A major pharmacologic consideration in HRT is RoA (route of administration)
 Oral dosage forms of estrogen go through portal circulation and thus expose liver
to high hormone concentations
 Also, oral admin. is assoc. w more rapid conversion of estradiol to estrone
 Transdermal estradiol overcomes PO problem of first-pass effect and still relieves
vasomotor , genitourinary symptoms and protects against bone loss
 Vaginally applied estrogen cream or tablets can be used to treat genitourinary
symptoms (vaginal dryness, atrophy & dyspareunia) but response may be lost
after 14 days b/c of tissue cornification or down-regulation of estrogen receptors
 Stopping Tx for 7 to 14 days and then restarting can overcome this effect
 N.B Conjugated estrogen vaginal cream and its equivalents have 4 times activity
of oral estrogens on local tissues

Estrogen or hormonal replacement therapy
159
N.B. Current EBM data states that overall health risks from HRT in
postmenopausal women appear to exceed possible benefits
Mechanism of action
 Reduces bone resorption
Uses
 Postmenopausal osteoporosis (reduces bone loss)
 Cannot restore bone
Adverse effects
 Similar to oral contraceptives but to a lesser extent because of lower
estrogen content
 The Women’s Health Initiative (WHI) Trial reported an increase in incidence
of strokes in both estrogen-alone and the estrogen-progestin subgroups as
compared with placebo groups.
 Thromboembolism

General Adverse Effects of Estrogens
160
 Doses of estrogen used in HRT are substantially less than those used in OCs, so
adverse effects of HRT tend to be less severe than those of OCs
 Estrogen may cause nausea, vomiting, edema, headache, hypertension, and
breast tenderness
 Estrogen is also a major cause of postmenopausal uterine bleeding is more
likely to occur during withdrawal period if estrogen is given cyclically w
progestin
 Progestin is likely responsible for edema and depression
 Androgen-like progestins can ↑ LDL/HDL ratio and cause thrombophlebitis,
hirsutism, weight gain, and acne

Cardiovascular and Neurologic Risks
162
 Risks and benefits of estrogen with regard to cardioprotection,
neuroprotection, and carcinogenicity in postmenopausal women
have been a subject of much debate
 Estrogen had been believed to be cardioprotective, possibly
through favorable changes in lipid metabolism and direct
vasodilatory effects
 However, the landmark trial (Women’s Health Initiative)
found estrogen-progestin HRT to be associated with an
increased risk of stroke, venous thromboembolism,
coronary heart disease, nonfatal myocardial infarction, and
death from heart disease

Estrogen CV and Neurologic Risks (2)
163
 The Women’s Health Initiative (WHI) Trial also indicated that
estrogen alone or w progestin did not affect progression of
atherosclerotic lesions in older postmenopausal women w
at least 1 coronary artery lesion
 Estrogen increased risk of Alzheimer disease a finding that
contradicts earlier data indicating a possible association
between estrogen and neuroprotection

Diagnosis of Stroke

Cancer Risk
165
Estrogen was shown in Women’s Health Initiative trial and another large
study to increase risk of breast cancer
 latter trial evaluated HRT in more than 1 million British women and found that those
who received HRT (especially both estrogen and progestin) had an increased risk of
development of and death resulting from breast cancer
risk of development of cancer increased w duration of HRT use, but it also
declined after discontinuation of HRT
 Trial indicated that estrogen-progestin reduced risk of colorectal cancer and
confirmed beneficial effects on reduction of hip and vertebral fractures
 However, these benefits do not outweigh risks
 As a result in 2003, US FDA urged clinicians to limit use of HRT to a few
months for temporary relief of postmenopausal symptoms

Key Points Summary
167
 Hormone replacement therapy is most effective treatment option for
alleviating vasomotor symptoms in postmenopausal women
 Risk of malignant tumors in women taking hormonal contraceptives is major
concern for use of these medications in perimenopausal women
 Although issue is still controversial it appears that there is a small duration-
related increase in risk of breast cancer
 This prompted U.S. FDA to mandate addition of new safety warnings to labels
of all systemic estrogens, including estrogen-only and combined
estrogen−progestin products
 Labels caution that “use of estrogen-containing hormone therapy regimens
by postmenopausal women may be associated with an increased risk of
breast cancer, myocardial infarction, stroke, and thromboembolism”

Hypogonadism
169
 In several conditions in females, such as Turner syndrome
(ovarian dysgenesis and dwarfism), ovaries do not develop
(or have no primordial follicles and may be represented only
by a fibrous streak) puberty does not occur
Other characteristics include:
 short stature
 primary amenorrhea
 sexual infantilism
 high gonadotropin levels, and
 multiple congenital abnormalities
 Conception is not possible

Hypogonadism (2)
170
 In males, dysfunction of Leydig cells or failure of hypothalamic
pituitary system can lead to inadequate secretion of
androgens testosterone replacement therapy is used
 If testosterone deficiency occurs before puberty results in
failure to complete puberty
 After completion of puberty testosterone defic. can lead to
o loss of libido and energy
o decreased muscle mass and strength
o decreased hematocrit and hemoglobin, and
o decreased bone mineral density

171
Hypogonadism examples
 Turner syndrome [female] (45,XO)
Menopause before menarche
↓estrogen leads to ↑LH, FSH
Short stature (if untreated), ovarian dysgenesis (streak ovary),
shield chest, bicuspid aortic valve, coarctation (femoral <
brachial pulse), lymphatic defects (result in webbed neck or
lymphedema in feet, hands), horseshoe kidney
Most common cause of 1° amenorrhea
 Klinefelter syndrome [male] (47,XXY)
Dysgenesis of seminiferous tubules↓ inhibin B↑ FSH
Abnormal Leydig cell function ↓testosterone ↑LH ↑
estrogen
Testicular atrophy, eunuchoid body shape, tall, long
extremities, gynecomastia, female hair distribution A
May present with developmental delay
Presence of inactivated X chromosome (Barr body)
Common cause of hypogonadism seen in infertility work-up

Hypogonadism Treatment & Adverse Effects
172
 For females, appropriate therapy with estrogen, usually w
progestin, replicates most events of puberty
 Genital structures grow to normal size, breasts develop, axillary and
pubic hair grows, and body achieves a normal FM contour
 Estrogen may increase growth, but if used too soon, it can
accelerate epiphyseal fusion cause a short final height
(treated w androgens and growth hormone)

Hypogonadism Tx & Adverse Effects (2)
173
For male testosterone deficiency, an oral drug is ineffective b/c
of liver metabolism
 Intramuscular testosterone (cypionate or enanthate) or
transdermal testosterone overcomes first-pass metabolism
to reach normal serum concentrations
Adverse effects
 In prepubertal children testosterone causes acne, hirsutism,
gynecomastia, and sexual aggression and growth disturbances
 Excess androgen in men can cause priapism or impotence, reduced
spermatogenesis, and gynecomastia
 Androgens can also cause edema and increased LDL/HDL ratio may
be harmful to those with CHF or hyperlipidemia, respectively

THE END
See next slide for further study.
174

Companion Tools and Resources (online)
175
eNotes
 Endocrine and Reproductive System Pharmacology
(NB: The reproductive section is companion to this presentation.)
MedPharm Guidebook
 Unit 8 Drugs Used In Disorders of Reproductive System
Case-based Learning
 Cases 40, 45, 51, 54
eLearning (cloud folders)
 M and FM Reproductive System & FM Breast
 Pregnancy, Childbirth, & the Puerperium

Drugs Used In Disorders of the Reproductive System

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