Join Dr. Licy Yanes-Cardozo as she expands on her research exploring the role of androgens on cardiovascular physiology in cis and transgender patients. Women have higher plasma concentrations of androgens than estrogens, yet the role of androgens in physiological processes and diseases is not completely understood. High levels of androgens in women are associated with a negative cardiometabolic profile, whereas in men, low levels of androgens are associated with an increased incidence of cardiovascular diseases.The biology behind androgens’ sex difference is not completely understood. In this webinar, Dr. Yanes-Cardozo discusses two clinical situations that are associated with high levels of androgens. Polycystic Ovary Syndrome (PCOS), the most common endocrine disorder in reproductive-aged women, is associated with a modest elevation of plasma levels of androgens. In transmen individuals (female to male), plasma concentrations of androgens are elevated to achieve similar levels found in cisgender men and much higher than in PCOS women. The role that these two different plasma concentrations play in cardiovascular physiology and pathophysiology remains unclear. Gaps and opportunities in basic research and clinical practice are highlighted. Key Topics Include: - Review the key role of androgens in cardiovascular pathophysiology - Discuss potential mechanisms by which androgens mediate a deleterious cardiometabolic profile in females - Interpret gaps and opportunities in basic and clinical practice in conditions of androgen excess

1. Cardiovascular Connections 2022
Androgens & Cardiovascular Diseases in Women:
From Basic Research to Clinical Practice
Licy Yanes Cardozo, MD
Associate Professor
Cell and Molecular Biology and Medicine/Endocrinology
University of Mississippi Medical Center

2. Partners and Sponsors

3. Copyright 2022. All Rights Reserved. Contact Presenter for Permission
Androgens & Cardiovascular
Diseases in Women: From Basic
Research to Clinical Practice
Licy Yanes Cardozo, MD
Associate Professor
Cell and Molecular Biology and Medicine/Endocrinology
University of Mississippi Medical Center

4. Androgens and Cardiovascular Diseases in
Women: From Basic Research to Clinical
practice
Licy L. Yanes Cardozo, MD
Associate Professor
Research Director - Center for Sexual and Gender Minority Center
Research Director - Internal Medicine Residency Program
Director - Women’s Health Research Center
Depts. of Cell & Molecular Biology and Medicine (Endocrinology)
University of Mississippi Medical Center

6. Outline
• Cardiometabolic complications due
to excess of androgens
• Hyperandrogenemia as a modifier of therapeutic
agents’ response
• Identifying high risk population for PCOS
complications

7. Androgen Secretion in Women
Androgens Daily
Amount
Dehydroepiandrosterone
sulphate (DHEAS)
3.5 to 20 mg/day
Dehydroepiandrosterone
(DHEA)
6–8 mg/day
Androstenedione (A) 1.4–6.2 mg/day
Testosterone (T) 0.1–0.4 mg/day
Dihydrotestosterone
(DHT)
4.3 and 12.5 mg/day
~500 ng/dl
Plasma
Testosterone
<200 ng/dl
~500 ng/dl
Transmen

8. Polycystic Ovary Syndrome (PCOS)
Rotterdam ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group. Hum Reprod. 2004;19(1):41-47
Azziz R et al. JCEM 2017
S a tis fa c tio n w ith in fo rm a tio n
g iv e n a b o u t m e d ic a l th e ra p y
D is s a tis fie d
o r
in d iffe re n t
S a tis fie d
In fo rm a tio n
n o t
m e n tio n e d

9. PCOS- Diagnosis Criteria

10. PCOS-Phenotypes
Diagnosis by
the Rotterdam Criteria,
two of three should be present:
• Polycystic ovarian Morphology (POM)
• Oligo/amenorrhea (OA)
• Hyperandrogenism (clinically and/or
biochemically) (HA)

11. Cardiovascular Risk Factors in PCOS
Dumesic et al, Endocr Rev, 2015;36:487-525
Elting et al, Hum Reprod, 2001;16:556-560
Song et al, Physiol Rep, 2019;7:e14219
Diagnosis by the Rotterdam Criteria, two of
three should be present:
• Polycystic ovarian Morphology (POM)
• Oligo/amenorrhea (OA)
• Hyperandrogenism (clinically and/or biochemically) (HA)

12. Oliver-Willems liverEuropean Journal of Preventive Cardiology 2020 Berni.et al.JCEM 2021
Cardiovascular Disease in PCOS
Average age: 26
Cardiovascular Disease Increased Risk
Myocardial Infarction 38%
Angina 60%
Revascularization 50%

13. Polycystic Ovary Syndrome
Diagnosed around puberty, irregular menses since then.
Hair growth : chin, chest , abdomen and thighs.
Combined and Progesterone only Oral Contraceptives à gain weight, worsening of hypertension and Diabetes, and heavy
menstrual bleeding. Spironolactone and laser therapy did not help with hirsutism.
T2DM
On metformin (insulin sensitizer) 1,000 mg orally twice a day since puberty.
T2DM diagnosed 2 years ago
Obesity
Body Mass Index: 41 (obesity >30)
Case Presentation
Wants to conceive soon
29 y.o. female diagnosed with Polycystic Ovary Syndrome (PCOS)
At endocrine clinic for management of poorly controlled Type 2 Diabetes Mellitus (T2DM) evaluation
Hypertension
Diagnosed 3 years ago
Blood Pressure: 123/68
on Lisinopril (Angiotensin Converting Enzyme Inhibitor) + Hydrochlorothiazide
Endocrine Office visit in 2017

14. Case Presentation - Labs
Testosterone, Total: 96 (2-45 ng/dl)
Testosterone, Free: 12.6 (0.1-6.4 pg/ml)
Glycated Hemoglobin A1c: 9.3% (pre-pregnancy goal <6.5%)

15. Teede et al. Human Reproduction 2018

16. Fasting Insulin
Guan et al. International Journal of Endocrinology 2020

17. T2DM
A1c: 9.3% on metformin
BP
Well controlled on Lisinopril (Angiotensin converting enzyme inhibitor)
High Testosterone levels
Desires pregnancy. Monitor
Will see Ob-GYN soon
Back to our patient
àStarted Glucagon Like Peptide 1
Receptor agonist (GLP-1RA, Liraglutide)

18. T2DM
A1c: down to 5.3 from 9.3% !!!
Several questions about of GLP-1RA and pregnancy?
Prefers to stop GLP-1RA
High Testosterone levels
Visit Ob-GYN for infertility, started on letrozole and Lisinopril was
stopped
Hypertension
BP 150/120 (off Lisinopril)
3 months treated with GLP-1RA (Liraglutide)

19. Glucagon like peptide-1 Receptor Agonist (Liraglutide)
Hyperandrogenemia as a modifier
of therapeutic agents’ response

20. Manneras L., et al. Endocrinology. 2007 Aug;148(8):3781-91 Yanes LL. et al. Gend Med, 2011(2): 103–115 Dalmasso C. et al. Endocrinology, 2016(7):2920-7
0 5 0 1 0 0 1 5 0
0
7 5
1 0 0
1 2 5
1 5 0
1 7 5
2 0 0
D H T
P la c e b o
*
*
*
O G T T
T im e (m in )
P
la
s
m
a
G
lu
c
o
s
e
(m
g
/d
l)
P la c e b o D H T
0
1 0
2 0
3 0
F a t M a s s
(E c h o M R I)
F
a
t
m
a
s
s
(
g
)
*
Days
1 2 3
MAP
(mm
Hg)
85
90
95
100
105
110
115
* *
*
DHT
Placebo
Treatment time (days)
0 5 10 15 20 25 30 35
Food
intake
(g)
0
5
10
15
20
25
Placebo
DHT
*
* *
*
*
Experimental Model of PCOS

21. Pleiotropic effects of GLP-1
Muskiet MHA, et al. Nature Rev Nephrol 2017

22. Torres-Fernandez et al. Endocrinology 2019
Yi Han et al. Reproductive Biomed 2019
GLP-1 RA and Cardiometabolic complications
in PCOS

23. CON HAF
0
1
2
3
4
GLP-1
(pM)
✱
Plasma GLP-1 levels are reduced in PCOS model

24. Adipose tissue GLP-1 Receptor is downregulated
in PCOS model
CON HAF
.0
.5
.0
CON HAF
0.0
0.5
1.0
1.5
GLP1R/
β-Actin
✱✱
Subcutaneous fat
CON HAF
0.0
0.5
1.0
1.5
2.0
Visceral Fat GLP-1R/β-Actin
Arbitrary
Units
0.0568
CON HAF
0.0
0.5
1.0
1.5
GLP1R/
β-Actin
✱
Perirenal fat Mesenteric fat
β-actin
GLP1R
β-actin
GLP1R
β-actin
GLP1R
CON HAF
0.0
0.5
1.0
1.5
GLP1R/
β-Actin
✱✱✱

25. Hyperandrogenemia as a modifier of
therapeutic agents’ response
Sodium-Glucose cotransporter Inhibitors (Empaglifozin)

26. Hyperandrogenemia Upregulates SGLT2 mRNA
Pruett et al 2021 Int.J. Mol.Sci.2021
Cortex Medulla
0
5
10
15
SGLT2/ActB
(AU)
PCOS - + - +
✱✱✱
✱✱✱

27. 0 5 10 15 20
0
100
200
300
400
500
Days of EMPA
Cumulative
Food
Intake
(g)
CON
CON+EMPA
PCOS
PCOS+EMPA
✱✱
✱✱
CON PCOS
0
100
200
300
400
500
Glucosuria
(mg/day)
✱✱✱✱
✱✱
✱✱✱✱
EMPA + - +
-
CON PCOS
0
2
4
6
8
HOMA-IR
EMPA + - +
-
✱✱
✱✱✱
CON PCOS
0
10
15
20
25
Fat
mass
(g)
EMPA + - +
-
✱✱
Pruett et al 2021 Int.J. Mol.Sci.2021

28. PPARγ: A key player in cardiometabolic complications
in PCOS

29. Pruett et al. Biology of Sex Differences (2022) 13:45
Differential effects on White Adipose Tissue (WAT)
of SGLT2 inhibition

30. Pruett et al. Biology of Sex Differences (2022) 13:45
Androgens decrease mitochondrial
activity in WAT
CON PCOS
0
2
4
6
8
HOMA-IR
EMPA + - +
-
✱✱
✱✱✱
Insulin Resistance

31. Renin Angiotensin System
Blood pressure
• 123/68 (on Lisinopril)
• 150/120 (off Lisinopril)

32. C
o
n
t
r
o
l
P
C
O
S
-50
-40
-30
-20
-10
0
Delta
MAP
(mmHg)
*
0 1 2 3 4 5 6 7 8
70
80
90
100
110
120
Day
MAP
(mmHg)
* * * * * * *
*
# # # # # # #
* * *
ACE-inhibition abolished the androgen-mediated
increase in blood pressure in PCOS
X

33. 0
0
5
10
15
20
25
30
8 12 16
Week
Fat
Mass
(g)
Control - Veh
Control - ENA
PCOS - Veh
PCOS - ENA
#
#
* *
ACE-inhibition abolished androgen-mediated
increase in fat mass but not IR in PCOS
Control PCOS
0
2
4
6
8
10
12
HOMA-IR
ENA + +
- -
*

34. Insulin Resistance and Fat mass In PCOS
Effect of Hyperandrogenemia
C
o
n
t
r
o
l
P
C
O
S
P
C
O
S
+
P
F
0
2
4
6
8
HOMA-IR
*
*
p=0.0573
EMPA: SGLT2 inhibitor
CON PCOS
0
2
4
6
8
HOMA-IR
EMPA + - +
-
*
*
Control PCOS
0
2
4
6
8
10
12
HOMA-IR
ENA + +
- -
*
ENA: Enalapril
C
o
n
t
r
o
l
P
C
O
S
P
F
-
P
C
O
S
0
10
20
30
Fat
mass
(g)
*
*
Control PCOS
0
5
10
15
20
25
30
Fat
Mass
(g)
* *
ENA + +
- -
Fat
Mass
HOMA-IR
Pair-Feeding

35. Torres-Fernandez et ak.Journal of the Endocrine Society 2018
Ex-DHT
DHT
6 months 6 months

36. Back to our patient
T2DM
A1c:8.7% (off GLP-1RA)à down to 6.5% on insulin pre
pregnancy
Hypertension
Labetalol (SNS/ alpha and Beta Blocker) - BP well controlled
IVF x 2 cycles à Pregnant
3/22/22: Fetal demise at 23 weeks of pregnancy
8/16/22: A1c 6.2% on Liraglutide and wants to conceive soon

37. Identifying high risk population for PCOS complications
Alabama California
Participants 134 189
BMI 31 34
mFG (Hirsutism) 5.6% 8.1%
Insulin Resistance 24% 37%
VanHise et al.Fertility and Sterility. 2020;114(3):e399

38. UMMC Research Data Warehouse (784,666 pts)
PCOS: ICD-10 Code: E28.2 (2,581 pts)
Inclusion Criteria
Patients with laboratory results:
Hb A1c, LDL, Free and Total Testosterone,
Triglycerides and ≤50years old

39. CAU AA
0.0
0.5
1.0
1.5
Free
Testosterone
(ng/dL)
P=0.05
n=90 n=178
CAU AA
0
18
23
28
33
38
43
48
BMI
(kg/cm
2
)
P<0.0001
n: 212 n: 273
CAU AA
90
92
94
96
98
100
MAP
(mmHg)
P<0.05
n: 212 n: 272
CAU AA
5.0
5.5
6.0
6.5
Hb
A1c
(%)
P<0.001
n: 248 n: 338
African American Women with PCOS have worse
Cardiometabolic Profile

40. Social Determinants of Health and PCOS

41. Cardiometabolic complications due to excess of androgens

42. A 41 year-old female seeking gender reassignment therapy with
testosterone. Female sex at birth but identifies as a male.
Patient states: at age 9 noticed that “something was wrong with my body”
“I felt I was a boy inside”.
Worsening of depression and anxiety.
Gender Dysphoria +
Physical Examination
Blood pressure: 150/94
Body Mass Index: 41 (obese)
Patient wants to start testosterone ASAP
Case Presentation: 2

43. J Clin Endocrinol Metab, November 2017, 102(11):3869–3903

44. Gender Dysphoria
Incongruence between gender identity and external sexual
anatomy at birth that causes psychological distress that
interferes with social, school, or other areas of function.

45. Gender-Affirming Therapy and Mental Health
Psychoneuroendocrinology 2014
Anxiety: 50% vs. 17% after GAT
Depression: 42% vs. 23% after GAT
80% reported significant improvement
in quality of life after GAT
Clin Endocrinol 2010

46. Testosterone is used in transmen to reach levels found in
cisgender men
Gender-Affirming Hormone Therapy (GAT)

47. GAT and Blood Pressure Regulation
Bank et al. Hypertension 2021
§ 247 TW and 223 TM, mean age: 27.8 years, office blood pressure
§ TM: Systolic 4.0 mmHg.
§ TW: Systolic 2.6 mmHg. Prevalence of Stage 2 hypertension decrease by 47%
TW: transwomen (Male-to-Female)
TM: transmen (Female-to-Male)

48. Outcomes for Transgender and Gender Expansive Adolescents
and Young Adults
Plasma Level of Testosterone and Estradiol

49. Insulin
Resistance
Hypertension
Obesity
Summary
Cardiometabolic Complications
Hyperandrogenemia
RAASx
SNSx
GLP-1RA
SGLT2-i
GLP-1RA
Adiponectin Agonists?

50. Acknowledgements
Edgar Torres Fernandez
Jacob E. Pruett
Ahmed M. Abdelhameed
Samar Rezq
Steven J. Everman
Kacey Davenport
Ruth Wilson
Alexandra M. Huffman
Noha Shawky
Medical Students Research
Program
Victoria Wilson
Savannah Stockton
Stephanie A. Ye
Sally McClung
Logan Ryals
Faridah Salau
Raksha N. Chatakondi
Jane F. Reckelhoff
Damian G. Romero
Deep South Center to Reduce
Disparities in Chronic Diseases
Analytical and Assay Core-UMMC
Barbara Alexander
Elizabeth Flynn
Sexual and Minority Heath Center-UMMC
Scott Rodgers
Alexander Mills
Nicholas Mcafee
Kayla Carr
Sharon McElvaun
Betsy Crosswhite
Naznin Dixit
Robert Santos
Jon Person
Mitochondrial Research Core-UMMC
Jonathan P. Hosler
Kristin Edwards
Ngoc Hoang
Medicine-UMMC
Lilian Lien
Vishnu Garla
Calvin Thigpen
Michael Hall
Biostatistics/Bioinformatics Core-UMMC
Seth Lirette
Norma Ojeda
Radiology-UMMC
Candace Howard-Claudio

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