Sean Thatcher, PhD

Sean.thatcher@temple.edu

Gonadal hormones and drugs

I do not have any conflicts to disclose.
At the end of the lecture, the student should be able to:
1. Explain the gametogenic and steroidogenic functions of the ovary and their regulation by the gonadotropins.
2. Identify the sources of androgens (ovary, testes, adrenal) and understand their regulation by the gonadotropins.
3. Describe medical issues associated with hypogonadism and explain rationale for replacement therapy.
4. Discuss the effects of oral contraceptives on cardiovascular function, intermediary metabolism, electrolyte and water balance, skin effects, and hepatic
function.
5. Discuss the effects of oral contraceptives on laboratory tests.
6. Discuss the effects of androgen in regards to “anabolic” versus “androgenic” effects.
7. Describe the common drug-drug interactions with oral contraceptives.
8. Describe the uses of estrogen and progesterone for post-menopausal replacement therapy.
9. Explain the rationale for various dosing schedules (monophasic, biphasic, triphasic) for oral contraceptives when combination estrogen-progestin
therapy is used.
10. Outline other types of hormonal contraceptive preparations including progestin only and postcoital agents.
11. Describe the use of long-acting progesterone for long term suppression of ovulation.
12. Explain the use of clomiphene for treatment of infertility.
13. Explain the clinical uses of androgens in hereditary angioedema, anemia, and catabolic states.
Follicle-stimulating hormone (FSH) and luteinizing -
hormone (LH) are the major hormones released by the
anterior pituitary in both men and women

• Gonadotropin-releasing hormone (GnRH) is Negative

released from the hypothalamus to Feedback
Loop
stimulate the anterior pituitary to release
FSH and LH. Pitocin® to induce
- labor
• Regulated by estrogen and progesterone
through negative feedback loops.
Negative Desmopressin
• There are GnRH agonists and antagonists Feedback (ADH analog)
used to treat
that can be used to treat reproductive Loop
central
diabetes
cancers (either), pulse therapy to treat insipidus

GnRH deficiency (agonist), and long-acting

formulations to inhibit gonadal function in Estrogen, Progesterone
children with precocious puberty
(antagonist). Sex hormones also follow biologic rhythms. Released in pulsatile manner.
 The ovary responds to gonadotropins and
estrogen/progesterone to release an ovum
• At the beginning of a cycle, a variable number of
follicles begin to enlarge in response to FSH.
• Follicles, under the influence of LH, will release
estrogens and one dominant follicle will emerge.
• At day 14 of the cycle, LH and FSH will surge and
cause ovulation. Remember that estrogen works by
positive feedback on LH and FSH at midcycle.
• The ovum will be released into the uterine tube. The
granulosa and thecal cells will produce estrogen and
progesterone (corpus luteum).
• Progesterone will increase the uterine lining and it
will become highly vascularized.
• If pregnancy does not occur, then a corpus albicans
forms and estrogen/progesterone production stops.
At day 28, the uterine lining will be shed, and
menses will occur.
Characteristics of estrogens
• Testosterone and estrogen differ
only by a methyl group, A ring, and
hydroxyl group on C3 of A ring.
• Estrogen interacts with two nuclear
receptors, ER⍺ and Erβ. These
receptors are found predominantly
in the nucleus.
• Most potent and naturally
occurring estrogens in the human
body are 17β-estradiol (E2), estrone
(E1), and estriol (E3).
 Estrogen signaling can occur through a
genomic and nongenomic signaling mechanism
• Estrogens can: GPER/GPR30
Estradiol
• Induce female sexual characteristics
• Endometrial growth
Src = tyrosine kinase
• Linear bone growth
• Inhibits bone resorption
• Increases coagulation Factor II, VII, VIII, X
• Increases fibrinogen
• Increase HDLs
• Decrease LDLs
• Decrease bile flow
• Decrease antithrombin III and protein S
• Decrease colonic motility (vasorelaxation of
smooth muscle)
• Salt and water retention
• Increases thyroid binding globulin levels which
will decrease free thyroid hormone levels Figure taken from ResearchGate
• Increases progesterone responsiveness
 Natural, steroidal synthetic, and nonsteroidal
synthetic estrogens
• Equine estrogens, also known as
conjugated equine estrogens (CEE) are
used most often for postmenopausal
hormone therapy.
• Can be used alone or with a progestin.
• Ethinyl estradiol is a common oral
contraceptive. Better oral absorption
and increased resistance to metabolism
occurs through ethylene group (arrows).
• Nonsteroidal synthetics are not used as
oral contraceptives; however, they may
be given to treat reproductive cancers
(part of the SERM family, e.g.,
Progesterone is derived from cholesterol and serves as a
precursor to the estrogens, androgens, and adrenocortical
steroids
• Progesterone can be
secreted from the ovary,
testis, and adrenal cortex.
Large amounts are also
released by the placenta
during pregnancy.
• Synthetic progesterones are
“19-nor” and “13-ethyl”
compounds and are used in
oral contraceptives.
Desogestrel and norgestimate are
typically given with ethinyl
estradiol for oral contraception
Progesterone signaling also occurs through a
genomic and nongenomic signal
• Progesterone can: Progesterone
• Maintains pregnancy
• Thickens cervical mucus
• Decreases thyroid binding
globulin and increases
activity of thyroid hormones.
• Increases metabolism
• Increases sodium and water
retention
• Increases basal temperature
during ovulation
• Decrease estrogen
responsiveness
Estrogens during the human lifespan
• *Contraceptives (30-40 years of treatment)
• *Hormone replacement therapy in post-menopausal women (3-5
years of treatment)

• There are also environmental chemicals and phytoestrogens that can

have estrogenic effects. These are found in our household products
and food.

Bisphenol A (BPA) chemical structure and

environmental chemical found in plastics (Wikipedia) Genistein, an isoflavone and phytoestrogen (Wikipedia)
Dosages and mechanism of action for
estrogens and/or progestins
Clinical indication
Primary hypogonadism
Postmenopausal therapy
Oral contraceptives
Transdermal patch (Ortho Evra®)
Implantable Progestin Preparation
Main mechanism of action for oral contraceptives to prevent ovulation which will prevent pregnancy.
Dosing
-0.3 mg CEE or 5-10 micrograms ethinyl estradiol (EE)
-Move to adult doses as patient ages
-0.3-1.25 mg/day of conjugated equine estrogens (CEE) or 0.01-0.02
mg/day of ethinyl estradiol (EE)
-Can also give 0.625 mg of CEE and 2.5 mg of medroxyprogesterone
acetate. Estrogens alone are taken on days 1-14 and combination on
days 15-28.
-Ethinyl estradiol given at 0.02-0.05 mg/day with Norethindrone at
0.4-1.5 mg/day
-Ethinyl estradiol at 0.02 mg/day and Norgestromin at 0.15 mg/day
-Etonogestrel (one tube of 68 mg)
Pharmacokinetics of estrogens
• Estradiol binds strongly to sex hormone-binding globulin with lower affinity to
albumin. Free fraction is the active form.
• Estrogens can be excreted in small amounts in breast milk of nursing mothers.
• Orally given estrogens undergo enterohepatic recirculation (thought to be why
there is increased coagulation factors and angiotensinogen).
• Due to extensive first-pass effects there are other routes of administration
(vaginal rings, transdermal patches, creams, or injection).
• Estrogens are mainly excreted via kidneys.
Pharmacokinetics of progesterone
• Rapidly absorbed and half-life is 5 minutes.
• High protein binding to albumin and transcortin (CBG). Free fraction
is active form.
• Can be found in breast milk of nursing mothers.
• Can be metabolized in the liver and conjugated to with glucuronic
acid. Can also undergo enterohepatic recirculation.
• Excreted mainly by the kidneys.
• Can be given in capsule/tablet, gel, vaginal ring/insert, and IM
injection.
 Clinical indications for estrogens and
progestins
• Primary hypogonadism used as replacement therapy
• Postmenopausal hormonal therapy
• Very controversial subject, WHI indicated adverse events with women that received HRT. Studies
seem to indicate that HRT should be given early on in menopause. Must evaluate cardiovascular risk
in female patients to determine if HRT is warranted.
• Oral contraceptives
• Must be taken every day for 21 days. The last 7 days consists of a placebo pill (e.g., sugar, iron pills).
Contraceptive pills do not protect against pregnancy during the first 7 days so an additional method of
birth control is recommended during this time (e.g., condoms).
• Ovarian suppression, dysmenorrhea, endometriosis, bleeding disorders, premenstrual
syndrome, premenstrual dysphoric disorder, polycystic ovarian syndrome (PCOS) and
hirsutism
• Progestins-only can be given in the treatment of dysmenorrhea, endometriosis, and
bleeding disorders when estrogens are contraindicated.
 Monophasic, biphasic, and triphasic uses of
oral contraceptives
• A drug preparation means that the drug is a chemically designed analogue of an
active agent. There are many different preparations for oral contraceptives.
• Two types of preparations for oral contraceptives:
• Combination of estrogens and progestins
• Continuous progestin therapy without concomitant administration of estrogens.

• Combination agents are further divided into:

• Monophasic  constant dosage of both components during the 21-day cycle
• Biphasic  dosage of one or both components changed once during the 21-day cycle
• Triphasic changed twice during the 21-day cycle
• Quadri-phasic is also a dosing schedule.
• These changes are to reflect the different estrogen-to-progestin ratios that occur during a
menstrual cycle. This also helped to reduce the overall total dose of the contraceptive.
Adverse effects of oral contraceptives
• Mild effects
• Nausea, breakthrough bleeding, mastalgia, and edema.
• Abdominal cramping
• Changes in serum proteins that could influence thyroid, adrenal, or pituitary
function
• Headache (migraines can develop in some cases)
• Failure to have a menses after withdrawal of the contraceptive (typically transient)
• Decreased libido
• Moderate effects
• Weight gain, increased skin pigmentation especially with UV light exposure, acne,
hirsutism, ureteral dilation, vaginal infections, amenorrhea (failure to have a
menses, secondary amenorrhea)
Severe adverse effects of oral contraceptives
• Thromboembolism
• Increases in Factors II, VII, VIII, X and fibrinogen. Decreases anti-thrombin III and protein S (anti-
coagulant proteins)
• Myocardial infarction
• This risk increases with women who smoke.
• Hypertension (increased renin and angiotensinogen)
• Higher glucose levels (moderate effect)
• Cerebrovascular disease
• Gastrointestinal disorders
• Cholestatic jaundice (progestin), cholecystitis, cholangitis, hepatic adenomas, ischemic bowel disease
secondary to thrombosis
• Depression
• Cervical cancer?
• Some studies indicate that cancer incidence can go up if oral contraceptive contains progestin. More
research is needed in this area.
Contraindications for oral contraceptives
• Uncontrolled hypertension
• Diabetics with vascular complications
• Smokers over the age of 35 (due to venous thromboembolism (VTE))
• Women with a history of VTE
• Women with known ischemic heart disease or valvular heart disease
• Women with active or a history of breast or endometrial cancer (or
any ER+/PR+ reproductive cancer)
• Women with have migraines with auras
 Drug-drug and lab-drug interactions with oral
contraceptives
• With oral contraceptives (drug-drug interactions)
• Warfarin concentrations can be increased when on oral contraceptives
• **Antibiotics altered enterohepatic cycling of estrogen metabolites Diminishes
efficacy of oral
• Rifampin increases liver catabolism of estrogens/progestins
contraceptives
• **Phenytoin increased catabolism of oral contraceptives
• Cimetidine is a P450 inhibitor inhibits estrogen metabolism

• Lab-drug interactions with oral contraceptives

• Can increase aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels
• Can alter lipid panels (TGs, HDLs, LDLs)
• Can alter prothrombin time (PTT, INR)
• Can alter T4 levels due to changes in thyroid-binding globulin
Long-acting progestins for suppression of
ovulation
• Two methods
• 150 mg of depot medroxyprogesterone acetate (DMPA) every 3 months
• SubQ implantation of capsules containing etonogestrel and last for 2-4 years
• Adverse effects with long-acting progestins are irregular bleeding.
• These drugs should not be used in women who want to have a pregnancy in
the near future.

Commonly referred to as the ”Depo shot”

Intrauterine devices (IUDs) can also be
utilized in contraception
• Two formulations
• Copper IUD
• Levonorgestrel IUD (Kyleena®, Mirena®)
• Typically last 3-6 years, copper IUD up to 10
years
• The copper IUD may be helpful for women that
have adverse effects with estrogens/progestins.
The copper IUD can also be inserted 5-7 days
after unprotected intercourse (postcoital agent).
• With the levonorgestrel IUD there is irregular
bleeding in the first 3-6 months after insertion.

Image taken from Drugs.com

Morning after pill and other postcoital agents
• Selective progesterone-receptor modulators (PRMs)
• Ulipristal (Ella®)
• Taken within 120 hours after intercourse. Available by prescription only.
• Plan B One-step®
• Two tablets of levonorgestrel (0.75 mg each)
• Can be taken within 72 hours after intercourse and can be obtained without a
prescription by women 18 years of age or older.
 Mifepristone, RU486, is a glucocorticoid
antagonist that also has an anti-progesterone effect
• Mifepristone, also a ”19-nor”, causes decidual
breakdown by blockade of uterine progesterone
receptors.
• If administered in the mid- to late luteal phase, it
will produce menses.
• Mifepristone is given in combination with
misoprostol (PG analog). Misoprostol is to ensure
expulsion of the detached blastocyst.
• Can be given for pregnancy termination within 49
days after the start of a woman’s last menses.
• Because RU486 is a glucocorticoid antagonist,
there is a black box warning if there are signs of
uterine infection. Have to treat aggressively with
antibiotics effective against anaerobic bacteria
(e.g., metronidazole). Taken from Medpage today
Clomifene for treatment of infertility
• Clomifene and Fulvestrant are antiestrogens used in the treatment of
infertility and tamoxifen-resistant breast cancer, respectively.
• Both of these agents bind to ER⍺ and Erβ and act as competitive
antagonists.

• Clomifene (oral administration) has a long half-life (5-7 days).

• This is largely due to enterohepatic recirculation and accumulation in fatty tissues
(Large volume of distribution, volume of distribution is approx. 57 Liters/kg)

• Fulvestrant is given by IM and maximum plasma concentrations are

reached after 7 days. Half-life ranges from 13.5-18.5 hours by IV.
Tamoxifen and other SERMs
• Tamoxifen has both agonist and antagonist
effects and is used as a chemotherapy in
breast cancer.
• It is a nonsteroidal agent given orally.
• Metabolized in the liver and through CYP2D6
(strong CYP2D6 inhibitors should be avoided
when taking tamoxifen).
• Toremifene is structurally similar to tamoxifen.
• Raloxifene can be used in treatment of
postmenopausal osteoporosis and as
prophylaxis of breast cancer in women with
high risk factors (e.g., Family history).
 Examples of estrogens/progestins used in
OCs
Estrogens Features
Estradiol valerate (E2V)
Ethinyl estradiol (EE)
Conjugated estrogens (CE)
Progestins
Medroxyprogesterone acetate (MPA)
Levonorgestrel (LNG)
Desogestrel (DSG)
Drosperinone (DSRP)
Dienogest (DNG)
Cyproterone acetate (CPA)
Synthetic estrogen that can be converted into 17β-estradiol, can be given IM or oral.
Synthetic estrogen, long duration of action
Natural estrogen, shorter duration of action compared to EE
Features
Can be given oral or IM. Blocks production of gonadotropins. Has androgenic and
glucocortropic activity
Progestin with androgenic activity. Used in IUDs
3rd generation progestin. Weak androgenic activity
Progestin that can act as aldosterone antagonist. Promotes natriuresis. Has
antiandrogenic activity.
Used in the long term treatment of endometriosis. Has antiandrogenic activity.
Has strong antiandrogenic activity. Used in the treatment of PCOS. Can be given IM or
oral.
Exemestane and anastrozole are aromatase inhibitors
that can be utilized to treat ovarian suppression
• Exemestane is a type I aromatase inhibitor (steroid
hormone). Anastrozole is a type II inhibitor and is
nonsteroidal.
• Pharmacotherapeutic uses:
• Early and late-stage ER+ breast cancer
• Adjunct with GnRH agonists in treatment of premature follicular
maturation (estrogen excess can block FSH/LH surge)
• MOA
• Aromatase inhibitors block the conversion of testosterone to
17β-estradiol (E2). Also blocks the conversion of
androstenedione to estrone (E1).
• Adverse effects
• Loss in bone mineral density, arthralgias, vaginal dryness, and
sexual dysfunction. Contraindicated in premenopausal women
with normal ovarian function.
Summary for female contraceptives and post-
menopausal therapy
• Estrogens and progestins can negatively feed back on gonadotropins (FSH, LH) and
GnRH, to suppress ovulation. This mechanism makes them utilized to prevent
unwanted pregnancy.
• There are many preparations and formulations of oral contraceptives. Dosing
schedules can be adjusted based on the needs of the patient. It is best to start
with the lowest dose possible to achieve the desired result.
• Estrogens/progestins can also be used in post-menopausal women however
duration of treatment is short and it is typically started early on in menopause.
This is still a very controversial issue and one that needs further research.
• Progestins can be given by themselves especially if estrogen will produce
unwanted side effects. There are both oral and injectable forms. Must look at the
androgenic and other steroid effects of these drugs. With patients that have
hirsutism, it is advisable to use a progestin that has anti-androgenic or no
androgenic activity.
Question #1
Which of the following patient profiles would NOT be contraindicated
for the use of oral contraceptives?
A. Patient that has migraines with light sensitivity.
B. Patient that is 42 yo and a heavy smoker.
C. Patient that has dysmenorrhea.
D. Patient that has been diagnosed with ER+ breast cancer.
E. Patient that is diabetic with atrial fibrillation.
Question #2
Which of the following lab results would NOT be influenced by the use
of oral contraceptives in a young female?
A. Measurement of thyroid-globulin levels
B. Pro-thrombin time
C. Measurement of LDL-C
D. Weight loss
E. Measurement of plasma AST/ALT levels
Question #3
3. A 52-year-old postmenopausal patient has evidence of low bone
mineral density. She and her physician are considering therapy with
raloxifene or a combination of conjugated equine estrogens and
medroxyprogesterone acetate. Which of the following patient
characteristics is MOST likely to lead them to select raloxifene?
A. Previous hysterectomy
B. Recurrent vaginitis
C. Rheumatoid arthritis
D. Strong family history of breast cancer
E. Troublesome hot flashes
Question #4
4. A young woman complains of abdominal pain at the time of
menstruation. Careful evaluation indicates the presence of
significant endometrial deposits on the pelvic peritoneum. Which
of the following is the most appropriate medical therapy for this
patient?
A. Flutamide, orally
B. Medroxyprogesterone acetate by IM
C. Norgestrel as an IUD
D. Raloxifene, orally
Male reproductive system
• Production of sperm is through the
secretion of FSH.
• With LH stimulation, testosterone will be
produced by interstitial or Leydig cells.
• Sertoli cells will make Mullerian duct
inhibitory factor, inhibin, and activin.
• Activin will stimulate FSH whereas inhibin
and testosterone will feedback to inhibit
FSH.
The testis, adrenal, and ovary can all produce
testosterone
• 8 mg of testosterone are produced daily in
men.
• Testis will also produce dihydrotestosterone
through 5⍺-reductase (potent androgen).
• Weaker androgens are DHEA and
androstenedione.
• Route of administration is IM or SubQ. Can
also give by transdermal patch or gels.
• Testosterone can:
• Increase skeletal muscle growth
• Increase secondary sex characteristics
• Increase linear bone growth
• Increase RBC production
Testosterone pharmacokinetics and metabolism
• 65% of circulating testosterone is bound to sex hormone-binding
globulin (SHBG). Some can also bind to albumin.
• 2% remains free and can bind to nuclear receptors.

• In target tissue, testosterone is converted to dihydrotestosterone

(DHT) by 5⍺-reductase. DHT produces the cellular effects.
• Major pathway for degradation occurs in the liver.
• Inactive metabolites are conjugated and excreted in the urine.
Therapeutic uses of testosterone
• Androgen replacement therapy in men (hypogonadism)
• Gynecologic disorders (endometriosis, chemotherapy)
• Protein anabolic agents (cancer cachexia)
• Anemia
• Osteoporosis (minor, bisphosphonates are largely used now)
• Growth stimulators (delayed puberty)
• Slowing the aging process
• Androgen abuse in sports (banned substance)
Contraindications of androgens
• Pregnant women or women who may become pregnant during the
course of therapy.
• Individuals with carcinomas of the prostate or breast (non-refractory
that can be treated with aromatase inhibitor or SERM).
• Developing children or infants
• Individuals with renal or cardiac disease that are predisposed to
edema.
• Hepatocellular carcinomas have been reported in patients with
aplastic anemia treated with androgen therapy.
Anabolic versus androgenic effects of male
steroid hormones
• Anabolic activity refers to the increase in cell growth (e.g., increase
protein synthesis, stimulation of bone marrow)
• Androgenic activity refers to the pattern of male sex (e.g., increase in
facial hair, voice deepening)
• Compounds with a high ratio of androgenic to anabolic effects are the
preferred drug of choice in androgen-replacement therapy.
• Compounds with a low ratio of androgenic to anabolic effects would
be utilized to treat anemia, osteoporosis, or to reverse protein loss.
Androgens used in the treatment of catabolism,
hereditary angioedema, and anemia
Androgen receptor antagonists and androgen
synthesis inhibitors (antiandrogens)
• Finasteride
• 5⍺-reductase inhibitor
• Therapeutic use is to reduce prostate
size in men with benign prostatic
hyperplasia and prevent male-pattern
hair loss in men.

• Flutamide (not a steroid)

• Competitive androgen receptor
antagonist
• Therapeutic use is the treatment of
prostate cancer. Can also be utilized in
women with androgen excess.
Summary for male androgens
• Testosterone will get converted by 5⍺-reductase to make DHT. DHT
will bind to androgen receptor to induce cellular effects.
• Testosterone can be made by the testis, adrenal, and ovary.
Aromatase functions to convert testosterone to estradiol.
• Androgens have differences in androgenic versus anabolic effects.
• Androgens can be utilized in the treatment of hyper-catabolism,
anemias, and hereditary angioedema.
• Finasteride can block the formation of DHT. Flutamide is a
competitive antagonist to the androgen receptor. Both can block
androgen effects and are listed as anti-androgens.
 Types of gonadal agonists and antagonists

Clomifene
Question #5
5. Men who use large doses of anabolic steroids are at increased risk of
which of the following?
A. Anemia
B. Cholestatic jaundice and elevation of AST in the blood
C. Hirsutism
D. Hyperprolactinemia
E. Testicular enlargement
Question #6
6. Finasteride has efficacy in the prevention of male-pattern baldness
by virtue of its ability to do which of the following?
A. Competitively antagonize androgen receptors
B. Decrease the release of gonadotropins
C. Inhibit the synthesis of testosterone
D. Reduce the production of dihydrotestosterone
FYI
GnRH analogs can be used in the treatment of
reproductive cancers and central precocious puberty
• GnRH analogs include:
• Gonadorelin, goserelin, buserelin, histrelin, leuprolide,
nafarelin, and triptorelin
• Can be given IV, SubQ, IM, and via nasal spray for
nafarelin.
• Can also be given via SubQ implant.
Chemical structure of Gonadorelin (Wikipedia)
• First 7-10 days of administration results in an
increase in FSH/LH referred to as a flare. After this
period, the continued presence of the analog will
result in inhibition and drop in FSH/LH and gonadal
steroids.
• Adverse effects include headache, light-headedness,
nausea, and flushing.
• Continuous treatment can induce symptoms of
menopause. Reduced bone mineral density and Chemical structure of Leuprolide (Wikipedia)
FYI
GnRH antagonists can be utilized in controlled
ovarian stimulation and advanced prostate cancer
• GnRH antagonists include:
• Ganirelix, cetrorelix, abarelix, and degarelix
• Given as SubQ doses
• Clinical indicated for preventing LH surge during controlled ovarian
stimulation.
• GnRH antagonists produce a more complete suppression of LH and
permit ovarian responses to stimulation. However, the effect can be
reversed more quickly and so patient adherence is critical.
• GnRH antagonists (degarelix, abarelix) are also approved for the
treatment of advanced prostate cancer.
 The End
Thank you for your attention!
Any questions?