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.
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.
Marc Imhotep Cray, MD 2
Topical Outline
 Key Sex Hormones & Related Drugs and Key Terms
 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
 Case-based Discussions/Learning
 Review Q&A (SBA)
Gonadotropins & Related Drugs
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

Sex hormones & Related Drugs cont’d.
PROGESTOGENS PROGESTOGENS cont.
Desogestrel (Used in Many Norgestrel (w/ethinyl estradiol)
Combinations) Progesterone (Used in Many
Drospirenone (w/ethinyl estradiol) Combinations)
Levonorgestrel Toremifene
Medroxyprogesterone Dienogest (w/estradiol valerate)
Norelgestromin (w/ethinyl estradiol) Etonogestrel (w/ethinyl estradiol)
Norethindrone Etonogestrel (subdermal)
Norethindrone acetate ANTIPROGESTOGEN
Norgestimate (Used in Many Mifepristone (RU-486)
Combinations) SELECTIVE PROGESTERONE
RECEPTOR MODULATOR (SPRM)
Marc Imhotep Cray, MD
Ulipristal acetate 7
Sex hormones & Related Drugs cont.
ANDROGENS ANTIANDROGENS
Danazol Bicalutamide
Fluoxymesterone Dutasteride
Methyltestosterone Finasteride
Oxandrolone Flutamide
Oxymetholone Nilutamide
Testosterone
Testosterone cypionate
Testosterone enanthate

Key Definitions & High-Yield Terms
 Androstanes: any 19-carbon steroid hormone, such as testosterone or
androsterone, which controls 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
Marc Imhotep Cray, MD and chemicals 9
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.
 SPRM: Selective progesterone receptor modulator. A group of drugs that
display tissue specific progesterone agonist or antagonist activity.
Transcriptional regulation by intracellular steroid hormone
receptors.
Whalen K. Lippincott Illustrated Reviews: Pharmacology, 6th Ed. Philadelphia, PA: Wolters Kluwer, 2015;352.
11
 5α-Reductase: 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
 Aromatase: A cytochrome P450 enzyme catalyzes conversion of
C19 androgens to aromatic C18 estrogens.
 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
 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
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
 Female hormone patterns are temporally more complex and

cyclic than male patterns:
o hormonal control of menstrual cycle is an illustrative example of how
sex hormones are integrated into a complex physiologic system
o Understanding the menstrual cycle also provides a basis for
understanding pharmacology of contraception
Organization of Reproductive System (2)
One example of 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

 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

Organization of
Reproductive System (3)
 Germinal epithelia of testes and
ovaries responsible for production of
sperm and ova (respectively)
 Various stromal cells of gonads are
responsible for production of
androgen and estrogen hormones
o 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
Raff 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
o Secrete inhibin B inhibit FSH
o Secrete androgen-binding protein maintain local levels of
testosterone
o Convert testosterone and androstenedione to estrogens via aromatase
= Homolog of female granulosa cells
 Leydig cells (endocrine cells) Interstitium
o Secrete testosterone in presence of LH= Homolog of female theca
interna cells
Regulation of Estrogen and Testosterone
Estrogen is synthesized in several forms estradiol, estrone and estriol
 Potency: estradiol > estrone > estriol
Many organs and processes in FM 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 20
Regulation of Estrogen and Testosterone (2)
 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)
Marc Imhotep Cray, MD Raff RB, Rawls SM, Beyzarov EP. Netter's Illustrated Pharmacology, Updated Edition.
22
Philadelphia: Sanders, 2014
Events of Normal Menstrual Cycle
As stated, understanding menstrual cycle provides a basis for understanding
pharmacology of contraception
 Start of cycle, cycle day 1= 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
o Estrogen inhibits pituitary it reduces gland’s release of LH
and FSH (negative feedback loop)…
Events of Normal Menstrual Cycle (2)
 …In midcycle, however, estrogen triggers a surge in
gonadotropin release (LH surge) from pituitary= a brief
positive feedback effect  stimulates follicular rupture
and ovulation
 Ruptured follicle becomes corpus luteum produces
progesterone (mostly) and estrogen under influence of LH
during second half of cycle (luteal phase)

Events of Normal Menstrual Cycle (3)
 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

Events of Normal
Menstrual Cycle (4)
 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.
26
Oocyte and Ovulation
Developing follicle
Stages of oocyte development and ovulation
27 2011
Smith PR & Turek PJ. The Netter Collection of Medical Illustrations: Reproductive System, Volume 1, 2nd Ed. Philadelphia, PA: Saunders-Elsevier,
Menstruation terminology
 Dysmenorrhea= Pain w menses often assoc. w 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
 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 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, progestogens 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
Steroid metabolism (steroidogenesis)
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.
P450scc
Marc Imhotep Cray, Lynn

MD Wecker et.al. Brody’s Human Pharmacology: Molecular to Clinical, 5th Ed. Philadelphia: Mosby, 2010 32
Reprod Pharm Overview (3)
 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 [SERMs]) have
different therapeutic uses, including
 prevention and treatment of breast cancer (tamoxifen) and
 prevention and treatment osteoporosis (raloxifene)
 Infertility assoc. w 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 w progestin)
replicates most events of puberty
 Testosterone replacement therapy is used for male patients w

hypogonadism
 Anti-androgens (flutamide) are used to treat androgen-

dependent cancers such as prostate carcinoma
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
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

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

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
Marc Imhotep Cray, MD luteum signals end of positive feedback 39
Negative and
Positive Feedback

Mulroney SE & Myers AK. Netter's Essential Physiology 2nd Ed. Philadelphia: Elsevier, 2016.
Gonadotropin-releasing hormone (GnRH)
 A decapeptide produced by neurons in preoptic area of hypothalamus
 Pulsatile secretion of GnRH from hypothalamus is essential for release of

gonadotropins--FSH and LH--from anterior pituitary
however,
 Continuous administration 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 provide
continuous delivery of drug
Gonadotropin-releasing hormone (2)
 Suppression of gonadotropins  leads to reduced production of gonadal
steroid hormones (androgens and estrogens)
Uses: 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
 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
approx. 6 months
NB: Remember pulsatile administration of GnRH
stimulates gonadotropin release, whereas continuous
administration GnRH inhibits LH and FSH release and
Marc Imhotep Cray, MD thereby blocks target cell function. 43
Gonadotropin-releasing hormone agonists (2)
 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
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

GnRH Antagonists cont’d.
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
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
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
Marc Imhotep Cray, MDof severe heart failure. Classified as a potassium-sparing diuretic. 48
Gonadotropins
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)
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

The hypothalamic-pituitary–reproduction axis.
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
Cairo CW, Simon JB, Golan DE. (Eds.). Principles of Pharmacology:
51
The Pathophysiologic Basis of Drug Therapy. LLW, 2012.
Gonadotropins (4)
 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.)
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 Cairo CW, Simon JB, Golan DE. (Eds.). Principles of Pharmacology:
The Pathophysiologic Basis of Drug Therapy. LLW, 2012.
epithelium (not shown) 53
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 The Pathophysiologic Basis of Drug Therapy. LLW, 2012.
54
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) 55
Gonadotropins (8)
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)
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
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

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 59
Prolactin Review (2)
Le T and Bhushan V. First Aid for the USMLE Step 1 2016 . McGraw-Hill 2016.
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
61
Answer & Educational Objective
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
Marc Imhotep Cray, MD Le T and Bhushan V. First Aid for the USMLE Step 1 2016 . McGraw-Hill 2016. 64
Gonadal Hormones & Antagonists: Overview
 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
Synthesis of progestins, androgens & estrogens
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 The Pathophysiologic Basis of Drug Therapy. LLW, 2012.
Steroid hormone receptors
 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
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
Marc Imhotep Cray, MD The Pharmacological Basis of Therapeutics. 12th ed. McGraw-Hill, 2011 68
Estrogens (prototype estradiol)
 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
 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
AllImhotep
Marc estrogens
Cray, MD are derived from aromatization of precursor androgens 70
Estrogens (3)
Estradiol
Estrone
Ethinyl Estradiol
Estrogen Synthesis
Johannsen EC & Sabatine MS. PharmCards: Review Cards

for Medical Students, 4th Ed. LLW, 2010.

Estrogens (4)
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)
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)
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)
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
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)
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
Anastrozole (Arimidex) aromatase inhibitor
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)
Johannsen EC & Sabatine MS. PharmCards: Review Cards for Medical Students, 4th Ed. LLW, 2010.
Estrogens estradiol and estrone from

Androgens androstenedione and testosterone
79
Aromatase inhibitors (3)
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
 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
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)
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
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
84
Progestins (3)
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)
 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 old
Marc Imhotep Cray, MD higher than that of testosterone. 86
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
87
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
Marc Imhotep Cray, MD Basis of Therapeutics. 12th ed. McGraw-Hill, 2011 88
Androgens (3)
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
Primary testicular failure such as result of
Clinical Use: bilateral anorchia, Klinefelter’s (XXY)
 Replacement therapy in hypogonadism karyotype, surgery, chemotherapy and
radiotherapy, or secondary testicular failure
 Anabolic agent (frequently abused)
as a result of hypothalamic– pituitary disease.
89
Androgens (4)
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
Androgens (5)
 Dehydroepiandrosterone (DHEA) and its
sulfate (DHEAS) and androstenedione are
adrenal steroids that are androgen
precursors
 DHEA and DHEAS have been marketed as Johannsen EC & Sabatine MS. PharmCards: Review
Cards for Medical Students, 4th Ed. LLW, 2010.
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 91
Flutamide (Eulexin) Anti-androgen
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
Marc Imhotep Cray, MD to ↓ hirsutism and in men to ↓ sexual drive (hypersexuality) 92
Flutamide (2)
Finasteride (Proscar) Anti-androgen
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)
Finasteride (3)
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
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
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

Incorrect Answers Explained
 (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
Endocrine Pharm. UWorld, 2014. 99
Combination Oral Contraceptives (COCs)
 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)
 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)
Raff RB, Rawls SM, Beyzarov EP. Netter's Illustrated Pharmacology, Updated
Marc Imhotep Cray, MD Edition. Philadelphia: Sanders, 2014 103
Major Adverse Effects of COCs
 Major effects, of excess or lack of estrogen or progestin, include
 breast fullness
 depression
 dizziness
 edema
 migraine, 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)
 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)

Marc Imhotep Cray, MD Updated Edition. Philadelphia: Sanders, 2014 106
Benefits COCs
 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
 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
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?
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, advisable to use a COC pill w 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
Marc Imhotep Cray, MD or switch to an IUD. 110
Estrogen and Coagulation
 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 NB: These actions augment risk of
thromboembolic disease in women
o protein S taking COCs about threefold compared
o plasminogen activator inhibitor protein I to women taking no hormones.
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
Marc Imhotep Cray, MD smoke and are older than 35 years 111
Estrogen and Coagulation (2)
Marc Imhotep Cray, MD Raff RB, Rawls SM, Beyzarov EP. Netter's Illustrated Pharmacology, Updated Edition. Philadelphia: Sanders, 2014 112
Estrogen and Coagulation (3)
Raff RB, Rawls SM, Beyzarov EP. Netter's Illustrated Pharmacology, Updated Edition. Philadelphia: Sanders, 2014

Progestin-Only Contraceptives
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)
 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)
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)
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)
Raff RB, Rawls SM, Beyzarov EP. Netter's Illustrated Pharmacology, Updated Edition.
Marc Imhotep Cray, MD Philadelphia: Sanders, 2014 119
“The Abortion Pill” [Mifepristone (RU-486)]
 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)
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
Marc Imhotep Cray, MD Updated Edition. Philadelphia: Sanders, 2014 121
Endometriosis
(ectopic growth of endometrium)
 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)
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
Endometriosis (3) Pelvis: Sites of Implantation
Klatt EC. Robbins and Cotran Atlas of Pathology, 3rd Ed.

Philadelphia: Saunders, 2015.
Raff RB, Rawls SM, Beyzarov EP. Netter's Illustrated

Pharmacology, Updated Edition. Philadelphia: Sanders, 2014
125
Endometriosis (4) Laparoscopic Views
Endometriosis Treatment (Danazol)
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)
Adverse effects
 characteristic of estrogen deficiency, include
 headache
 flushing
 sweating
 atrophic vaginitis
 Androgenic side effects include

 acne
 edema
 hirsutism
N.B. Although danazol highly effective in relieving
 deepening of voice
symptoms of endometriosis, newer, better-
 weight gain
tolerated treatments have reduced its use.

COCs and Progestins
 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)
 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
 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)
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

Estrogen Decline
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 N.B. Menopause assoc. symptoms include hot flashes,
 osteoporosis vaginal atrophy, osteoporosis, and coronary artery disease
(Remember, menopause causes HAVOC: Hot flashes,
Atrophy of Vagina, Osteoporosis, and Coronary artery
Marc Imhotep Cray, MD disease) 137
Pituitary & Ovarian Hormone Changes in Menopause
Pharmacology, Updated Edition. Philadelphia: Sanders, 2014

 In postmenopausal period, FSH &L H levels ↑ and ovarian
 Hormone levels ↑ and ↓ cyclically during menstrual cycle
hormone levels ↓ secondary to ovarian failure
 Modulation occurs by pulsatile release of gonadotropins
 Endogenous estrogen is primarily of adrenal origin, and E1 to
and positive and negative feedback loops
E2 ratio is reversed
Vasomotor Symptoms
 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
 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
 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)
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
Role of Progestins in Hormone Replacement
Therapy (HRT)
 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

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
147
Estrogen or hormonal replacement therapy
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
 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
 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)
 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
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
Raff RB, Rawls SM, Beyzarov EP. Netter's Illustrated Pharmacology, Updated Edition.
Philadelphia: Sanders, 2014
Key Points Summary
 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”
Selective Estrogen Receptor Modulators
 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)
 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
Antiestrogens
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
Marc symptoms, visual disturbances and (multi-birth pregnancy )
Imhotep Cray, MD 161
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
Hypogonadism
 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)
 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

Hypogonadism examples
 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
 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
Pharmacology, Updated Edition. Philadelphia: Sanders, 2014 166
Hypogonadism Treatment & Adverse Effects
 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)
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 2 slides for further study.

Companion Tools and Resources (online)
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
 Case Files Pharmacology Cases 40, 45, 51, 54
eLearning (cloud folders)

 M and FM Reproductive System & FM Breast
 Pregnancy, Childbirth, & the Puerperium

Further study:
Textbooks
 Brunton LL, Chabner BA , Knollmann BC (Eds.). Goodman and Gilman’s The
Pharmacological Basis of Therapeutics. 12th ed. New York: McGraw-Hill, 2011
 Katzung, Masters, Trevor. Basic and Clinical Pharmacology, 12th ed. New York:
McGraw-Hill, 2012
 Mulroney SE. and Myers AK. Netter's Essential Physiology. Philadelphia:
Saunders, 2009
 Raff RB, Rawls SM, Beyzarov EP. Netter's Illustrated Pharmacology, Updated
Edition. Philadelphia: Sanders, 2014
 Toy E C. et.al. Case Files-Pharmacology Lange 3rd ed. New York: McGraw-Hill
2014.

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Photo: Color-enhanced scanning electron micrograph of a human oocyte.

Marc Imhotep Cray, MD 6

Marc Imhotep Cray, MD 8

 Estranes: any 18-carbon steroid hormone, such as estradiol and estrone,

 Pregnanes: any 21-carbon steroid hormone, such as progesterone, responsible

 Cytochrome P450, CYP: any of a large number of enzymes produced from

 HREs: Hormone response elements. specific nucleotide sequences, residing

 SERM: Selective estrogen receptor modulator. A group of drugs that display

 Anabolic steroid Androgen receptor agonists used for anabolic

 Breakthrough bleeding Vaginal bleeding that occurs outside of

 Hirsutism A male pattern of body hair growth (face, chest,

 HRT (Hormone replacement therapy) refers to estrogen

 necessary for conception, embryonic maturation, and

 Female hormone patterns are temporally more complex and

Marc Imhotep Cray, MD 16

 Testosterone, main androgen in humans, is synthesized and

 Testosterone secretion is also controlled by hypothalamus-

Marc Imhotep Cray, MD 17

 triggers anterior pituitary to release gonadotropins= LH and FSH

 Testosterone resulting from steroidogenesis inhibits

Marc Imhotep Cray, MD 21

In follicular (or proliferative) phase, hypothalamus releases

Marc Imhotep Cray, MD 24

 Conception causes progesterone secretion to continue with

 Without conception corpus luteum stops progesterone

Marc Imhotep Cray, MD 25

 Follicular growth is fastest during 2nd

 Oligomenorrhea > 35-day cycle

 Polymenorrhea < 21-day cycle

 Metrorrhagia= Frequent or irregular menstruation

 Menorrhagia= Heavy menstrual bleeding > 80 mL blood loss or >

 Menometrorrhagia= Heavy, irregular menstruation

 Key concepts include:

Marc Imhotep Cray, MD 30

Marc Imhotep Cray, Lynn

 Certain hormone-like drugs whose estrogenic activities are tissue

 In female patients with failure of ovarian development

 Testosterone replacement therapy is used for male patients w

 Anti-androgens (flutamide) are used to treat androgen-

Marc Imhotep Cray, MD 35

These pituitary hormones determine development of

Marc Imhotep Cray, MD 37

Marc Imhotep Cray, MD 38

 Prime example of positive feedback occurs during

Marc Imhotep Cray, MD 40

 Pulsatile secretion of GnRH from hypothalamus is essential for release of

 GnRH agonists have hypoestrogenic side effects, eg, mild

Marc Imhotep Cray, MD 44

Marc Imhotep Cray, MD 45

Marc Imhotep Cray, MD 46

Marc Imhotep Cray, MD 47

Incorrect Answers Explained

 Actions and pharmacologic properties

Marc Imhotep Cray, MD 50

 In each case, a two cell system is coordinated to mediate

 Testosterone then diffuses into nearby Sertoli

 ABP stabilizes high concentrations of

 Androgen then diffuses into nearby granulosa

 FSH increases aromatase activity in granulosa

Marc Imhotep Cray, MD 56

Marc Imhotep Cray, MD 57

Marc Imhotep Cray, MD 58

 Function Stimulates milk production in breast, inhibits ovulation in females and

 Regulation Prolactin secretion from anterior pituitary is tonically inhibited by dopamine

Marc Imhotep Cray, MD 62

 Androgens include dehydroepiandrosterone