Lecture: Women's Health, Hormones and Sexuality

Home , Cimetidine, Glutamine, Pregnenolone

Anna M. Cabeca, DO, FACOG, ABAARM

Hot Topics in Women's Sexual Health

Anna Cabeca, DO, FACOG, ABAARM

ACOFP Conference, Las Vegas, March 2015

CabecaHealth.com/Docs

Key Points

 Physiology drives behavior – testosterone and libido and relationships

 Vaginal androgen hormone therapy is restorative  Stress and the cortisol – oxytocin connection

1 7 Key Areas of Sexual Health

Physical Psychol- Medical ogical

SEXY! Environ- Emotional mental

Spiritual Relational

My Story - BEFORE • 40 year old with 4 children • Worked over 80 hrs/week • Primary bread winner • Losing hair • 80 lbs overweight • Menopausal and infertile • Depressed

2 The soul suffers when the body is diseased or traumatized, while the body suffers when the soul is ailing - Aristotle

My Story - AFTER

• Hair grew back • Lost over 80 lbs • Fertile again… meet my miracle - Ava! • Wake up excited each morning

3 DS – Case Presentation  1999 – 64 y.o WF h/o DCIS rt breast at age 58  Cc: Vaginal dryness, decreased libido, diminished orgasm, sex very important to her, relationship suffering as a result  PMHx: DCIS, FCBD  PE: 5’10” 155 lbs, vulvar atrophy. Clitoral atrophy

DS – Case Presentation  1999 Labs:  E2 < 20, P <1, T 0.0,  SHBG, DHEA-S wnl

 Tx: Estradiol vag cream 2/wk  Testosterone 2.5 mg sl  Progesterone cream 20 mg  EROS ctd

4 EROS -Clitoral Therapy Device

DS – Case Presentation  2009 74y – 2/16 OH E ratio 2.85  Salivary test  DHEA low, cortisol nl  CPM, DHEA 25 mg /day  Maca and Greens  Adrenal supplement  Carnitine 1000mg bid  MVIT/min, omega, vit D

5 DS – Case Presentation

 Dexascan results:

2000 2009 Change (64y) (73y) T - Spine -0.5 -0.4 +0.7%

T - Hip 0.0 -0.5 -3.0%

VM – Case presentation  62 y.o WF consult re: vaginal pain  Meds: Klonopin, Crestor, Zetia, Prilosec, Ultram, aspirin, vaginal estrogen 2 x/ week  PMHx: Migraines, hyperlipidemia, hypertriglyceridemia, GERD  PShx: TAH/LSO age 30 –endometriosis & ov cyst  Age 55y. Cysto/recto repair

6 VM – Case Presentation  Labs: Hormones low, TSH 3.85, Free T4 1.0, Free T3 2.6, Trg 245  PE: vaginal atrophy, diminished clitoris, suture palpable sq.

 Tx: Bi-est 1.25 mg + P 30 mg + T 1mg vag suppository w/ Emu oil  Iodine, thyroid support, Omega’s, Krill…

Normal Sexual Function  Good Health  Hormone Balance  Comfortable with body  Able to communicate desires  Has an interest in sex  Arousable  Adequate vaginal lubrication  Able to achieve orgasm

7 Decline of DHEA with aging

8 Effect of intravaginal dehydroepiandrosterone (Prasterone) on libido and sexual dysfunction in postmenopausal women

Menopause: The Journal of The North American Menopause SocietyVol. 16, No. 5, pp. 923/931  Abstract DOI: 10.1097/gme.0b013e31819e85c6 2009 by The North American Menopause Society

 Objective: The objective of this study was to provide evidence that the transformation of DHEA into both androgens and/or estrogens locally in cells of the three layers of the vagina (epithelium, lamina propria, andConclusions: muscularis) would have By effects a oflocal greater impact, action including in effects the on sexualvagina, function, than onlyDHEA effects on superficial applied epithelial daily cells as achieved at doses with estrogens. at which  Methods: This prospective, randomized, double-blind, and placebo-controlled phase III clinical trial has evaluated the effect of daily local intravaginal application of Prasterone (dehydroepiandrosterone; DHEA) forserum 12 weeks on steroids the domains of sexual remain dysfunction, well namely, within desire/interest, normal arousal, orgasm, and pain at sexual activity, in 216 postmenopausal women with moderate to severe symptoms of vaginal atrophy.postmenopausal values exerts relatively

 Results: potentA time- and dose beneficial-dependent improvement effects of the four on domains all of four sexual function aspects was observed. At the 12-week time interval, the 1.0% DHEA dose led, compared with placebo, to 49% (P = 0.0061) andof 23% sexual dysfunction. Such data indicate  (P = 0.0257) improvements of the desire domains in the Menopause Specific Quality of Life and Abbreviatedthat Sex Functioncombined questionnaires, androgenic/estrogenic respectively. Compared with placebo, the Abbreviated Sex Function arousal/sensation domain was improved by 68% (P = 0.006), the arousal/lubrication domain by 39% (Pstimulation = 0.0014), orgasm by 75% in (P the= 0.047), three and dryness layers during intercourse of the by 57% vagina (P = 0.0001).

 Conclusions:exerts By a local important action in the vagina, beneficialDHEA applied daily ateffects doses at which on serum sexual steroids remain well within normal postmenopausal values exerts relatively potent beneficial effects on all four aspects of sexual dysfunction. Such data indicate that combined androgenic/estrogenic stimulation in the threefunction layers of the vagina in exerts women important beneficial without effects on systemic sexual function in action women without systemicon action the on the brainbrain and other and extravaginal other tissues. extra -vaginal tissues.

Endocrine and intracrine sources of androgens in women: inhibition of breast cancer and other roles of androgens and their precursor dehydroepiandrosterone

 Endocr Rev. 2003 Apr;24(2):152-82.

 Labrie F, Luu-The V, Labrie C, Bélanger A, Simard J, Lin SX, Pelletier G.

 Molecular Endocrinology and Oncology Research Center, Laval University Medical Center (Centre In Hospitaliera series de l'Université of Laval) animal and Laval University, models, Québec City, Québec androgens G1V 4G2, Canada. In [email protected] studies, DHEA has been found to

 Serum androgens as well as their precursors and metabolites decrease from the age of 30-40 yr in increaseandwomen, DHEA thus suggesting bone thathave minerala more physiological been density hormone found replacement and totherapy toinhibit at menopause should contain an androgenic compound. It is important to consider, however, that most of the androgens in women, especially after menopause, are synthesized in peripheral intracrine tissues from the inactive precursors dehydroepiandrosterone (DHEA) and DHEA sulfate (DHEA-S) of adrenal origin. Much progress in this new area of endocrine physiology called intracrinology has followed the cloning and breaststimulatecharacterization cancer ofvaginal most of the enzymesdevelopment maturation responsible for the transformation without and of DHEA growth and DHEA-S into androgens and estrogens in peripheral target tissues, where the locally produced sex steroids are exerting their action in the same cells in which their synthesis takes place without significant diffusion into the circulation, thus seriously limiting the interpretation of serum levels of active sex steroids. The sex affectingsteroids made in theperipheral endometrium, tissues are then inactivated locally whileinto more water improving-soluble compounds that anddiffuse to into thestimulate general circulation where bone they can be measured.formation. In a series of animal models, androgens and DHEA have been found to inhibit breast cancer development and growth and to stimulate bone formation. In clinical studies, DHEA has been found to increase bone mineral density and to stimulate vaginal maturation without affecting the endometrium, while improving well-being and libido with no wellsignificant-being side effects. and The advantage libido of DHEA withover other androgenic no significant compounds is that DHEA, at physiological doses, is converted into androgens and/or estrogens only in the specific intracrine target tissues that possess the appropriate physiological enzymatic machinery, thus limiting the action of the sex steroids to those tissues possessing the tissue-specific profile of expression of the genes responsible for their formation, while leaving the other tissues unaffected and thus minimizing the potential side sideeffects effects. observed with androgens or estrogens administered systemically.

9 DHEA and the intracrine formation of androgens and estrogens in peripheral target tissues: its role during aging.

 Steroids. 1998 May-Jun;63(5-6):322-8.

 Labrie F, Bélanger A, Luu-The V, Labrie C, Simard J, Cusan L, Gomez JL, Candas B.

 Laboratory of Molecular Endocrinology, CHUL (Le Centre Hospitalier de l'Université Laval) Research Center, Québec, Canada. [email protected]

Furthermore, Human and some other primates the are unique inhibitory since their adrenals secrete largeeffect amounts of dehydroepiandrosterone of DHEA (DHEA) and its sulfate (DHEA-S), which are converted into androstenedione (4-dione) and then into potent androgens and estrogens in peripheral tissues, therefore providing autonomous intracrine control to target tissues that can adjust the formation and metabolism of active sex steroids according to local requirements. Knowledge in this area has recently made rapid progress with the elucidation of the structure of most of the tissue-specific cDNAs and genes that encode the steroidogenic enzymes on responsiblethe growthfor the transformation ofof these inactivehuman precursor steroids breast into androgens cancer and/or estrogens. It is estimated that 30 to 50% of total androgens in men are synthesized in peripheral intracrine tissues from inactive adrenal precursors while, in women, peripheral estrogen formation is even more important, the best estimate being 75% before menopause and 100% after menopause. The marked reduction in the formation of DHEA-S by the adrenals during aging, especially before the age of 50 years, results in a dramatic fall in the formation of active sex steroids in peripheral target tissues, a situation which is xenograftsthought to be associated inwith a longvivo series of age in-related nude decreases such mice as insulin resistance, supports obesity, osteoporosis, the cardiovascular diseases, loss of muscle mass, cancer and other diseases. We have demonstrated for the first time a series of medically important beneficial effects of DHEA administered for 12 months to post-menopausal women. Most interestingly, the bone mineral density significantly increased. This relatively rapid change was associated with an increase in plasma osteocalcin, a marker of bone formation, while a decrease in bone resorption reflected by a decrease in urinary hydroxyproline excretion was observed in parallel. In addition, the estrogenic stimulation of vaginal cytology in the absence beneficialof any sign of stimulatory use effect on ofthe endometrium DHEA is also of potentially as majorhormone interest for the prevention and management of menopause. Furthermore, the inhibitory effect of DHEA on the growth of human breast cancer xenografts in vivo in nude mice supports the beneficial use of DHEA as hormone replacement therapy in women.

replacement PMID: 9618795 [PubMed - indexed therapy for MEDLINE] in women.

Psychological Causes of Sexual Dysfunction  What are their ideas about sex?  How were they raised?  What were their early sexual messages?  Were they victims of sexual abuse?  What are their religious and cultural beliefs?  How is their relationship with their partner?  Are they able to communicate their needs?

10 Physical Causes of Sexual Dysfunction  Inflammatory diseases  Elevated cholesterol, ADMA, —affecting arterial blood flow

 History of pelvic surgery  History of episiotomy or child birth trauma  Trauma  Fatigue  Headaches/Pain

Medication Induced Sexual Dysfunction

 Anti-Androgen drugs: flutamide, GNRH analogues, cytotoxic chemotherapeutic agents

 Psychoactive drugs and mood stabilizers  Sedative-hypnotics: alcohol, benzodiazepines, sleeping pills

 Antidepressants: SSRIs, Tricyclics

11 Medication Induced Sexual Dysfunction

 Antihypertensive Agents: Hydrochlorothiazide, beta blockers

 Drugs that bind with testosterone or increase SHBG levels: Tamoxifen, hormonal contraceptives, oral estrogens

 Others: Cimetidine, steroids, aldosterone, lovastatin

Statin tx lowers libido  April 16, 2010 -- Statin therapy prescribed to lower cholesterol also appears to lower testosterone, according to a study that evaluated nearly 3,500 men who had erectile dysfunction or ED.

 ''Current statin therapy is associated with a twofold increased prevalence of hypogonadism," - Giovanni Corona, MD, PHD, a researcher at the University of Florence in Italy

12 Sexual Dysfunction During Menopause

 Decline in progesterone age 35-40  Estrogen Dominance  Testosterone insufficiency  Elevated SHBG  Thyroid Hormone abnormality  Decline in DHEA  h/o childhood trauma, lack of bonding, PTSD

Hormonal Causes of Sexual Dysfunction  Estrogen  Progesterone  Testosterone  DHEA  Cortisol  Thyroid hormones  Oxytocin  Vitamin D

13 Balancing Hormones

Adrenaline Cortisol Insulin

Estrogen Progesterone Testosterone DHEA Melatonin Oxytocin Vitamin D Pregnenolone

Do Hormones Help More than Hot Flashes?

 257 women studied over a 10 year period.  All domains of sexual function declined significantly in the decade studied. Women using hormone therapy had significantly greater responsivity and higher frequency of sexual activities than nonusers.  Hormone therapy helps women maintain sexual function and response.  Sexual distress as determined on the Sexual Distress Scale was associated with higher incidence of depression and relationship conflicts.

Dennerstein, et al. Sexual Function, Dysfunction, and Sexual Distress in a Prospective, Population. BasedSample of Mid-Aged, Australian-Born Women. J Sex Med. 2008 Jul 14

14 Menopause. 2008 Jan- Feb;15(1):23-31.

 Decreased androgen concentrations and diminished general and sexual well-being in women with premature ovarian failure.  van der Stege JG, Groen H, van Zadelhoff SJ, Lambalk CB, Braat DD, van Kasteren YM, van Santbrink EJ, Apperloo MJ, Weijmar Schultz WC, Hoek A.  Department of Obstetrics and Gynaecology, Meander Medical Center, Amersfoort, The Netherlands. [email protected]  OBJECTIVE: To describe general and sexual well-being in women with premature ovarian failure (POF) and to investigate whether there is a relationship between androgen levels and sexual functioning. DESIGN: Women with POF and healthy volunteers with regular menstrual cycles participated. Participants completed a written questionnaire and Multiple regressionunderwent analysis hormonal screening. revealed The questionnaire thatincluded standardizedandrogen measures: the Questionnaire for Screening Sexual Dysfunctions, the Shortened Fatigue Questionnaire, and the Symptom Check List-90. Serum hormone measurements included estradiol, total levels had only testosterone,a weak bioavailable influence testosterone, androstenedione,on sexual dehydroepiandrosterone, and dehydroepiandrosterone sulfate. RESULTS: Eighty-one women with POF and 68 control women participated in the study. Compared with control women, women with POF functioning; higherreported moretotal complaints testosterone of anxiety, depression, somatization,levels sensitivity, were hostility, and psychological distress. Overall women with POF were less satisfied with their sexual life. They had fewer sexual fantasies and masturbated less frequently. Sexual contact was associated with associatedincreased with less sexual frequency arousal, reduced lubrication, of desire and increased for genital pain. However, the frequency of desire to have sexual contact and the frequency of actual sexual contact with the partner did not differ between women with POF and control sexual contact, andwomen. Womenhigher with POF androstenedione had lower levels of estradiol, total testosterone, levels and androstenedione. Multiple regression analysis revealed that androgen levels had only a weak influence on sexual functioning; higher total testosterone levels were associated with increased frequency of desire for sexual contact, and higher androstenedione levels were were associatedassociated with with elevated elevated frequency frequency of sexual contact. CONCLUSIONS: of sexual Women with POF have diminished general and sexual well-being and are less satisfied with their sexual lives than control women. Although women with POF had lower androgen levels, we did contact. not find an important independent role for androgens in various aspects of sexual functioning. © 2014 Dr Anna Cabeca

Practice medicine that makes sense!

Oxytocin – Stress – Cortisol Connection

16 Better than an apple a day!

Chronic stress and cortisol

 Cortisol is actually what wakes the brain up in the morning.

 AF is mediated by a constant ON signal from the circadian circuitry in mitochondria connecting to the brain.

 AF is a electromagnetic disease of having no OFF switch for light or high powered photons.

 Chronic lowered cortisol is not a symptom but the reaction of the brain to this stimulus.

 This is why the PVN down regulated cortisol over time to stop the potential short circuiting of mitochondria.

17 Fight Flight Freeze Rest & Digest

Feed & Breed

Tend & Befriend

Oxytocin The Love and Bonding Hormone

Nurturing-Attachment-Relationship Pleasure Mood enhancing, happiness, kindness Appetite reduction Pain relief Orgasm, increase in clitoral/penile sensitivity to sexual arousal Increases muscles Anti-aging effects

18 Oxytocin Calms the Effects of Stress

 In Stress- oxytocin concentrates at the CNS areas rich in cortisol (hippocampus)

 Oxytocin binds to receptors, inhibiting specific neurons, lowering levels of Oxytocin and ACTH

 Less responsive to Stress

 Over time there is depletion and disintegration of oxytocin

oxytocin

cortisol

19  Salvaori, R. Adrenal Insufficiency. JAMA. 2005;294(19):2481-2488.

 Helm C, et al; Pituitary-Adrenal and autonomic response to stress in Women After sexual and physical abuse in childhood. JAMA. 2000;284(5):592-597/ http://jama.jamanetwork.com/article.aspx?articleid=192947&resultClick=3

 Maunder RG, Levenstein S. The role of stress in the development and clinical course of IBD: Epidemiologic evidence. Current Molecular Medicine 2008, 8, 247-252.

 McFarlane AC. The long-term costs of traumatic stress: Intertwined physical and psychological consequences. World Psychiatry 12 Mar 2013. http://onlinelibrary.wiley.com/doi/10.1002/j.2051-5545.2010.tb00254.x/full

 Melamed, S, et al. Burnout and risk of cardiovascular disease: Evidence, possible causal paths, and promising research directions. Psychological Bulletin, Vol 132(3), May 2006, 327- 353. http://dx.doi.org/10.1037/0033-2909.132.3.327

 Jenny NS. Inflammation in Aging: cause, effect or both? Discovery Medicine. June 25, 2012. http://www.discoverymedicine.com/Nancy-S-Jenny/2012/06/25/inflammation-in-aging-cause- effect-or-both/

Monday Morning Practice

 Address sexual health concerns and validate them (Treat the couple!)

 Discuss vaginal changes  Offer vaginal hormone therapy  Vaginal DHEA  Vaginal estrogen  Compounded combinations  Refer to virtual education programs patients can do on their own time and privacy of their home

20 Vaginal hormonal treatment options  Compounded DHEA vaginal suppositories/tablets or topical cream  5-10 mg  Testosterone  0.5 – 10 mg suppository (higher doses with incontinence)  Estriol/Estradiol  Progesterone  Oxytocin  Ex: Bi-est 0.5 mg+ T 2mg + DHEA 3mg combined

Non-hormonal treatments for vaginal dryness  Coconut oil  Ayurvedic Ghee  Yes

21 Monday Morning Takeaways  Stress causes NT, hormone, and cell membrane Δ’s   Progesterone (bonding),  CL- efflux from cell and Ca++ into cell   Cortisol… eventually downreg by PVN (revving engine)  Glutamine synthetase glutamte availability (excitatory aa)  Disrupt neuronal energetics,  oxidative damage   Inflammation  Telomere attrition   Oxytocin  Disconnect  Sense that body/brain betrays you… mind betrays you… your soul suffers

Monday Morning Takeaways

 Key tests:  DHEA-S  Vit D 25-hydroxy  Hs CRP  HgbA1c  Salivary cortisol  AA/EPA ratio  Comprehensive hormonal panel

22 Monday Morning Takeaways  Nutrients to decrease inflammation, support cell membrane integrity and function and adrenal function  DHA  Maca  Quercetin  Resveratrol  Grape Seed extract  Turmeric  Supplements  Vit D  Progesterone and/or Pregnenolone  DHEA

Treatment Approaches  Hormonal  Nutrition—reduce processed foods, increase whole, organic free range foods  Herbal/botanicals  Increase omega-3 intake  Exercise—increases circulation and strength  Kegel Exercises  Detoxification—cleanse liver, heal gut

23 Herbal/Botanical Treatments

 wild yam,  red clover,  damiana,  urtica dioca,  standardized tribulis,  Korean ginseng,  epimedium (horny goat  deer antler, weed),  gingko biloba,  DIM

 Maca

Ginkgo biloba special extract EGb 761 in the treatment of peripheral arterial occlusive disease (PAOD)--a review based on randomized, controlled studies.Horsch S, Walther C.Int J Clin Pharmacol Ther. 2004 Feb;42(2):63-72. Review. © 2014 Dr Anna Cabeca

MACA  Menopause. 2008 Nov-Dec;15(6):1157-62. Links

 Beneficial effects of Lepidium meyenii (Maca) on psychological symptoms and measures of sexual dysfunction in postmenopausal women are not related to estrogen or androgen content.  Brooks NA, Wilcox G, Walker KZ, Ashton JF, Cox MB, Stojanovska L.  School of Biomedical and Health Sciences, Victoria University, St. Albans, Victoria, Australia.  OBJECTIVE: To examine the estrogenic and androgenic activity of Lepidium meyenii (Maca) and its effect on the hormonal profile and symptoms in postmenopausal women. DESIGN: Fourteen postmenopausal women completed a randomized, double-blind, placebo-controlled, crossover trial. They received 3.5 g/day of powered Maca for 6 weeks and matching placebo for 6 weeks, in either order, over a total of 12 weeks. At baseline and weeks 6 and 12 blood samples were collected for the measurement of estradiol, follicle-stimulating hormone, luteinizing hormone, and sex hormone-binding globulin, and the women completed the Greene Climacteric Scale to assess the severity CONCLUSIONS:of menopausal symptoms. In addition, aqueousPreliminary and methanolic Maca findings extracts were tested for androgenic and estrogenic activity using a yeast-based hormone-dependent reporter assay. RESULTS: No differences were seen in serum concentrations of showestradiol, that follicle -stimulatingLepidium hormone, luteinizing meyenii hormone, and(Maca) sex hormone -(3.5binding globulin between baseline, Maca treatment, and placebo (P > 0.05). The Greene Climacteric Scale revealed a significant reduction in scores in the areas of psychological g/d)symptoms, reduces including the psychological subscales for anxiety and depression symptoms, and sexual dysfunction after Maca consumption compared with both baseline and placebo (P < 0.05). These findings did not correlate with androgenic or alpha-estrogenic activity present in the includingMaca as no physiologically anxiety significant and activity depression, was observed in yeast-based and assays employing up to 4 mg/mL Maca extract (equivalent to 200 mg/mL Maca). lowersCONCLUSIONS: measures Preliminary findings of showsexual that Lepidium dysfunction meyenii (Maca) (3.5 g/d) reduces psychological symptoms, including anxiety and depression, and lowers measures of sexual dysfunction in postmenopausal women independent of estrogenic in andpostmenopausal androgenic activity. women independent of estrogenic and androgenic activity.

24 Top 11 Ways to Increase Oxytocin 1. Orgasm 2. Contraction/Labor/Breast Feeding (nipple suckling) 3. Sexual Contact, Vaginal Distention

4. Love -romantic -maternal/paternal

5. Laughter 6. Playfulness -Music, dance, movement, singing

7. Massage 8. Hugging, caressing, physical contact 9. Charity

10. Partnership/Family/Community 11. Food Intake- distention of the stomach stimulates the vagus nerve, allow time between meals.

Life lived fully is  Love  Learning  Lessons  Legacy  Laughter

25 Dr. Anna M. Cabeca Email [email protected]

For a copy of my slides and helpful handouts: www.CabecaHealth.com/docs

Garrett V. Bivens Foundation

Healthy Mom & Strong Healthy Baby & Teaching Tots to Swim

www.CabecaHealth.com

womensrestorativehealth.com

26 CabecaHealth.com/docs

@Dr Anna Cabeca 2/23/2015 53