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Sexual Vitality: It’s All About ChemistryNeuroendocrine Solutions for a Strong and Lasting Sex Life

Robyn Kutka, NDLead Staff PhysicianLabrix Clinical Services, Inc.

Learning Objectives

• Understand the extent of sexual concerns as they exist in the U.S. population

• Gain insight into origins of common sexual complaints• Learn to assess and accurately treat functional conditions associated with sexual dysfunction

• Obtain successful treatment protocols utilizing natural hormone therapies

• Become familiar with plant‐based medicines and pharmaceutical interventions

Simply defined, sexuality is the quality or state of being sexual; the expression of sexual receptivity or interest.

A Common Concern

Sexual dysfunction is a common concern among both sexes throughout the years:

31% of menand

43% of womenreport experiencing sexual dysfunction at some point during

their lifetimes

American Society for Reproductive Medicine. Sexual dysfunction and infertility. Available at: http://www.asrm.org/Sexual_Dysfunction_and_Infertility/ . Accessibility verified October 17, 2012.

Huge Interest

• K‐Y Intense is sold in Walmart, Walgreens and Rite Aid

• Sensuva (an arousal oil for women) can be found in 640 GNC stores nationwide

• Intimina products (sexual care line) is sold at Pharmaca, CVS and drugstore.com

• Zestra (an arousal oil) is now sold in 1800 Walmartsup from 880 in 2010 and previously endorsed by Kris Jenner (Kardashian)

New York Times. More women look over the counter for a libido fix. Available at: http://www.nytimes.com/2012/07/03/health/more‐women‐seek‐over‐the‐counter‐sexual‐remedies.html?_r=1&emc=eta1Accessibility verified October 17, 2012.

Sexual Dysfunction May Adversely Impact Quality of LifeLowered ego, self‐worth, and self‐esteem, as well as a significant reduction in life satisfaction and quality of the couple's relationship

MongaM, et al. Impact of infertility on quality of life, marital adjustment and sexual function. Urology. 2004; 63: 126‐30.

Sexual Dysfunction

• Sexual dysfunction occurs when there is a disturbance within the sexual response cycle

Masters WH, Johnson VE. Human Sexual Response. New York, NY: Little, Brown: 1966.

Linear Model of Sexual Response

1. Desire2. Arousal3. Orgasm4. Resolution

Association of Reproductive Health Professionals. Handbook on female sexual health and wellness. Available at: http://www.arhp.org/uploadDocs/ARHP_ACOG_SexualityHandbook.pdf . Accessibility verified October 17, 2012.

A Universal Fit?

• Presumes men and women have similar sexual responses• Does not account for non‐biologic experiences such as pleasure and satisfaction

• Does not place sexuality in the context of the relationship• Many women do not move sequentially through these phases

Association of Reproductive Health Professionals. Handbook on female sexual health and wellness. Available at: http://www.arhp.org/uploadDocs/ARHP_ACOG_SexualityHandbook.pdf . Accessibility verified October 17, 2012.

Association of Reproductive Health Professionals. Female Sexual Response. Available at: http://www.arhp.org/publications‐and‐resources/clinical‐fact‐sheets/female‐sexual‐response Accessibility verified October 17, 2012.

Non‐Linear Model of Sexual Response• Incorporates the importance of:

• Emotional intimacy• Sexual stimuli• Relationship satisfaction

Non‐Linear Model of Sexual Response

• Prevents diagnosing dysfunction when the response is simply different from the traditional human sex‐response cycle

• More clearly defines subgroups of dysfunction; which is necessary before progress in newer treatment modalities, including pharmacological, can be made

Basson R. The female sexual response: a different model. J Sex Marital Ther. 2000; 26: 51‐65.

Sexual Dysfunction

• More common among women than men• Associated with:

• Age• Education• Poor physical health• Poor emotional health

Shifren JL, et al. Sexual problems and distress in United States women: prevalence and correlates. Obstet Gynecol. 2008; 112: 970‐78.

Causes of Sexual Dysfunction

• Consider changing biology and life challenges:• Physical/medical• Lifestyle/social• Psychological

Woods NF, et al. Sexual desire during the menopausal transition and early postmenopause: observations from the Seattle Midlife Women’s Health Study. J Womens Health (Larchmt). 2010; 19: 209‐18.

Physiological Causes of Sexual Dysfunction

• Hormone imbalance• Neurotransmitter imbalance

• Diabetes• Metabolic syndrome• Obesity• Hypertension• Neurologic disordersMayo Clinic. Female sexual dysfunction. Available at: http://www.mayoclinic.com/health/female‐sexual‐dysfunction/DS00701/DSECTION=causes . Accessibility verified October 18, 2012. Natural Practitioner. An alternative approach to sexual function. Available at: http://digitaledition.qwinc.com/display_article.php?id=1036176 . Accessibility verified October 18, 2012.

• Cardiovascular disease

• Endocrine disorders

• Autoimmune disorders

• Chronic fatigue

• Fibromyalgia

• Cancer

• Dyspareunia

Lifestyle Causes of Sexual Dysfunction

• Medications• Anti‐depressant (particularly SSRIs) meds, anti‐hypertensives, oral birth control pills

• Alcoholism and substance abuse• Amphetamines, barbiturates, cocaine, marijuana, heroin

• Tobacco use• Sleep difficulties• Pregnancy, childbirth, parenting

Mayo Clinic. Female sexual dysfunction. Available at: http://www.mayoclinic.com/health/female‐sexual‐dysfunction/DS00701/DSECTION=lifestyle‐and‐home‐remedies . Accessibility verified October 18, 2012. Woods NF, et al. Sexual desire during the menopausal transition and early postmenopause: observations from the Seattle Midlife Women’s Health Study. J Womens Health (Larchmt). 2010; 19: 209‐18.Woolhouse H, et al. Women's experiences of sex and intimacy after childbirth: making the adjustment to motherhood. J PsychosomObstetGynaecol. 2012 Sep 13

Psychosocial and Sociocultural Causes of Sexual Dysfunction

• Depression• Anxiety• Stress and fatigue• Relationship turmoil• Absence of sexual satisfaction

Mayo Clinic. Female sexual dysfunction. Available at: http://www.mayoclinic.com/health/female‐sexual‐dysfunction/DS00701/DSECTION=causes. Accessibility verified October 18, 2012. Woods NF, et al. Sexual desire during the menopausal transition and early post‐menopause: observations from the Seattle Midlife Women’s Health Study. J Womens Health (Larchmt). 2010; 19: 209‐18.

• Negative change in self‐perception

• Negative change in self‐confidence

• Low support system

• Social and religious influences; upbringing

Male Sexual Dysfunction

• The most common sexual concerns among men include:

• Erectile dysfunction (ED)• 18% of all non‐diabetic and 50% of diabetic men over the age of 20 experience ED

• Ejaculatory dysfunction• Decreased libido

• 13.5% (dyadic)

American Society for Reproductive Medicine. Sexual dysfunction and infertility. Available at: http://www.asrm.org/Sexual_Dysfunction_and_Infertility/ . Accessibility verified October 17, 2012. Martin S, et al. Clinical and biopsychosocial determinants of sexual dysfunction in middle‐aged and older Australianmen. J Sex Med. 2012; [Epub ahead of print].Selvin E, et al. Prevalence and risk factors for erectile dysfunction in the US. Am J Med. 2007; 120: 151‐57. 151‐7

Who is at risk for ED?

Major risk factors include:• Age• Smoking • Obesity

Mayo Clinic. Erectile dysfunction. Available at: http://www.mayoclinic.com/health/erectile‐dysfunction/DS00162/DSECTION=risk‐factors. Accessibility verified October 18, 2012.

1st Line Therapy?

PDE5‐inhibitors are typically recommended as first line therapies with or without androgen therapy

Boston University School of Medicine. Sexual dysfunction in men. Available at: http://www.bumc.bu.edu/sexualmedicine/informationsessions/sexual‐dysfunction‐in‐men . Accessibility verified October 18, 2012.

ED and Comorbidities

• Established cardiovascular disease

• Atherosclerosis• Hypertension• Dyslipidemia• Hyperlipidemia

ED is often accompanied by comorbid conditions including:

Fine SR. Erectile dysfunction and comorbid diseases, androgen deficiency, and diminished libido in men. J Am Osteopath Assoc. 2004; 104: S9‐15.

• Diabetes mellitus• Depression• Lower urinary tract symptoms

• Status post‐prostatectomy for prostate cancer

Testosterone and ED

• In the absence of comorbid diseases that may cause ED, “testosterone therapy is effective in restoring sexual desire and function”

• Testosterone therapy alone provides 35‐40% success rate of reversing erectile dysfunction

• Supplementation may increase the efficacy of phosphodiesterase type‐5 inhibitors (PDE5‐I) in those men where PDE5‐I’s alone fail (30‐40%)

Albrecht‐Betancourt M, et al. Androgen replacement in men with hypogonadism and erectile dysfunction . Endocrine. 2004; 23: 143‐8.Guay, AT. Testosterone and erectile physiology. Aging Male. 2006; 9: 201‐6.

Testosterone and Comorbidities

In men with type 2 diabetes, TRT significantly improves:• HbA1c• Total cholesterol• Weight circumference

Beyond Testosterone

When evaluating, initiating supplementation and monitoring testosterone levels in men, hormone balance is key.

• Estradiol – monitor levels for aromatization• Studies of castrated men suggest estrogen is required for erection!

• Progesterone – testing and supplementation consideration for prostate health

• DHEA – support of testosterone levels when needed• Studies suggest ED support in those with no organic etiology

• Cortisol – evaluate for adrenal dysfunctionLee JR. Hormone Balance for Men: What Your Doctor May Not Tell You About Prostate Health and Natural Hormone Supplementation. Temecula, CA: One to One Inc.; 2007.

Cortisol

Adrenal hypofunction resulting in suboptimal ‐ low cortisol levels may impact libido in both men and women:

Suboptimal Cortisol

Suboptimal Cortisol FatigueFatigue

Decreased libido!

Decreased libido!

**Don’t forget to consider depressed thyroid function**unction**

Leproult R, Van Cauter E. Effect of 1 week of sleep restriction on testosterone levels in young healthy men. JAMA. 2011; 305: 2173‐74.

Progesterone

Progesterone assists to modulate male sexual function:• Influences spermatogenesis, sperm capacitation and testosterone biosynthesis in Leydig cells

Andersen ML, Tufik S. Does male sexual behavior require progesterone? Brain Res Rev. 2006 Jun;51(1):136‐43.

Progesterone

2006 Review:

“This review opens a window on progesterone as a potential hormone that exerts a considerable influence on male sexual function…

…in recent years, studies have provided valuable insight of progesterone modulating male sexual function”

Andersen ML, Tufik S Does male sexual behavior require progesterone? . Brain Res Rev. 2006 Jun;51(1):136‐43. Epub 2005 Dec 28.

Botanical and Nutraceutical TX Options

• Supplementation to decrease oxidative stress and inflammatory markers (increase NO production, lower insulin resistance):

• Antioxidants• Omega‐3 fatty acids• Folate• Vitamin D

Meldrum DR, Gambone JC, Morris MA, Esposito K, Giugliano D, Ignarro LJ.Int J Impot Res. Lifestyle and metabolic approaches to maximizing erectile and vascular health. 2012 Mar‐Apr;24(2):61‐8.


• L‐arginine • High dose (5 g qd x 6 weeks) shown to provide subjective improvement in ED by 31%

• *Considered contraindicated with history of HSVChen J, et al. Effect of oral administration of high‐dose nitric oxide donor L‐arginine in men with organic erectile dysfunction: results of a double‐blind, randomized, placebo‐controlled study. BJU Int. 1999; 83: 269‐73.

• Korean Red Ginseng • (1 g tid x 12 weeks) improved erectile function without detectable changes to testosterone, prolactin or cholesterolde Andrade E, et al. Study of the efficacy of Korean Red Ginseng in the treatment of erectile dysfunction. Asian J Androl. 2007; 9: 241‐44.


L‐arginine and Pycnogenol 40 men ages 25‐45 with ED, no “organic cause”

• All took 1700 mg L‐arginine daily for 3 months • Second month, Pycnogenol 40 mg, BID added to L‐arginine• Third month, Pycnogenol 40 mg, TID added to L‐arginine

Stanislavov R, et al. Treatment of erectile dysfunction with pycnogenol and L‐arginine. J Sex Marital Ther. 2003; 29: 207‐13.


L‐arginine and PycnogenolResults

Normal erections reported by:• 2 of 40 participants after 30 days (arginine alone) • 32 of 40 after 60 days (arginine & Pycnogenol 80 mg) • 37 of 40 (92%!) after 90 days (arginine & Pycnogenol 120 mg)

”L‐arginine in combination with Pycnogenol causes a significant improvement in sexual function in men with ED without any side effects.”Stanislavov R, et al. Treatment of erectile dysfunction with pycnogenol and L‐arginine. J Sex Marital Ther. 2003; 29: 207‐13.


L‐arginine and Pycnogenol

Japanese men with mild to moderate ED • 690 mg L‐arginine, 60 mg Pycnogenol and 552 mg aspartic acid PO QD

• After 8 weeks of supplementation:• Marked improvement in “hardness of erection” and “satisfaction of sexual intercourse”

• Decrease in blood pressure, aspartate transaminase and y‐GTP• Slight increase in salivary testosterone levels• No adverse reactions observed

Aoki H, et al. Clinical assessment of a supplement of Pycnogenol® and L‐arginine in Japanese patients with mild to moderate erectile dysfunction. Pytother Res. 2012; 26: 204‐7.

Arginase

Concentrated in the liver and intestine, the enzyme that converts arginine to ornithine (rather than NO) is upregulated with ED comorbidities:• Presence of oxidized LDL, hypertension, atherlosclerosis, diabetic vascular disease

Cormio L, De Siati M, Lorusso F, SelvaggioO, Mirabella L, Sanguedolce F, et. al. Oral L‐citrulline supplementation improves erection hardness in men with mild erectile dysfunction. Urology. 2011 Jan; 77(1):119‐22

Another Option?

L‐citrulline• Converted to l‐arginine in thekidneys, vascular endothelium

• Does not induce arginaseactivity, thus increases amount of arginine available for NO production

Schwedhelm E, Maas R, Freese R, et al. Pharmacokinetic and pharmacodynamic properties of oral L‐citrulline and L‐arginine: impact on nitric oxide metabolism.Br J Clin Pharmacol. 2008 Jan;65(1):51‐9.


L‐cirtrulline

24 males with mild ED mean age 56.5+/‐ 9.8 years• Given placebo for 1 month and L‐citrulline, 1.5 g/d, for another month

• Increase in erection hardness score from 3‐4 in 50% of men when taking L‐citrulline (compared to 8.3% when taking placebo)

Cormio L, De Siati M, Lorusso F, SelvaggioO, Mirabella L, Sanguedolce F, et. al. Oral L‐citrulline supplementation improves erection hardness in men with mild erectile dysfunction. Urology. 2011 Jan; 77(1):119‐22

Additional Treatment Considerations

• Methylation support• 5‐MTHF, methylB12 and B6

• Support homocysteine levels (homocysteine lessens NO production)

• Support BH4 stability/production (co‐factor for NOS)

Longevity Medicine Review. Managine Erectile Dysfunction – When Viagra Doesn’t. Available at: http://www.lmreview.com/articles/view/managing‐erectile‐dysfunction‐when‐viagra‐doesnt#fn‐114‐12. Accessibility verified February 13, 2014.

Lifestyle Considerations

• These lifestyle changes alone may result in improved sexual function in 1/3 or obese men with ED:

• Weight loss (body mass index less than 30)• Increased physical activity• Dietary intervention: Mediterranean diet, alcohol consumption

• Additional considerations:• Smoking cessation• Psychotherapy

Esposito K. Effect of lifestyle changes on erectile dysfunction in obese men: a randomized controlled trial. JAMA 2004; 291: 2978‐84.Meldrum DR, Gambone JC, Morris MA, Esposito K, Giugliano D, Ignarro LJ. Lifestyle and metabolic approaches to maximizing erectile and vascular health. Int J Impot Res. 2012 Mar‐Apr;24(2):61‐8.

Healthy Lifestyle

Reduces Risk&

Treats ED

Esposito K. Effect of lifestyle changes on erectile dysfunction in obese men: a randomized controlled trial. JAMA 2004; 291: 2978‐84.

Female Sexual Dysfunction

• 43% of women report sexual dysfunction at some point in their lifetimes

• Including lack of desire, arousal or orgasm, or pain during intercourse

• Postpartum, breastfeeding and menopausal hormonal changes often parallel symptoms

• More symptomatic women (hot flashes, fatigue, sleep and mood disturbances) report significantly lower sexual desire

Edward O, et al. Sexual dysfunction in the United States: prevalence and predictors. JAMA. 1999; 281: 537‐44.Woods NF, et al. Sexual desire during the menopausal transition and early post‐menopause: observations from the Seattle Midlife Women’s Health Study. J Women’s Health. 2010; 19: 209‐18.

FSD• Multicausal• Multidimensional

Association of Reproductive Health Professionals. Female Sexual Response. Available at: http://www.arhp.org/publications‐and‐resources/clinical‐fact‐sheets/female‐sexual‐response Accessibility verified October 17, 2012.

Female Sexual Dysfunction

The most prevalent sexual problems among women age 50+ are:

• Decreased libido (43%)• Difficulty with vaginal lubrication (39%)

• Inability to climax (34%)

AARP. Sex, romance and relationships: AARP survey of midlife and older adults. Available at: http://assets.aarp.org/rgcenter/general/srr_09.pdf. Accessibility verified October 24, 2012.

Decreased libido….DSM IV

Hypoactive Sexual Desire Disorder is the “persistently or recurrently deficient (or absent) sexual fantasies and desire for sexual activity” that causes a woman “marked distress or interpersonal difficulty”• 1:10 US women affected

Clayton AH. The pathophysiology of hypoactive sexual desire disorder in women. Int J Gynecol Obstet. 2010; 110: 7‐11.

Decreased libido….DSM V

Controversial changes to the diagnostic criteria of FSD include:• Combining Female Sexual Arousal and Desire Disorder into one disorder

• Requires presence of disorder for 6 months or more

Outside a Diagnosis

When distress is not accounted for, concern about low sexual desire may be present in up to 40% of women

Pressman P. Med LPC, Gambescia PhD, RN. Hypoactive Sexual Desire Disorder in Women: An evolving Understanding. Infertility & Reproductive News April 2011 Vol 3, Number 2.

Libido & Hormones: Balance is key!

Hormones and neurotransmitters are excitatory or inhibitory in nature and optimal sexual functioning requires a balance of these factors.• Excitatory:

• Estrogen• Progesterone• Testosterone• Dopamine• Norepinephrine and epinephrine• DHEA

• Inhibitory:• Serotonin• GABA• Cortisol

Clayton AH. The pathophysiology of hypoactive sexual desire disorder in women. Int J Gynecol Obstet. 2010; 110: 7‐11.

Libido and hormone therapy

Women using hormonal therapy report higher sexual desire• Individualized therapy is needed; every woman is not the same and thus testing is necessary to assess individual needs

Woods NF, et al. Sexual desire during the menopausal transition and early post‐menopause: observations from the Seattle Midlife Women’s Health Study. J Women's Health. 2010; 19: 209‐18.

A Balancing Act

Hormone imbalance and female sexual dysfunction is more than just testosterone!

• Contributing hormonal imbalances may include:• Estrogen deficiency• Estrogen dominance• Hyper/hypoandrogenism• Cortisol dysregulation• Thyroid dysfunction

Lee JR. What Your Doctor May Not Tell You About Menopause. New York, NY: Warner Books; 2004.

Estrogen Deficiency

Estrogen replacement is the prescribed therapy for most of the sexual dysfunction observed in menopausal women

Aswar UM, et al. Estrogenic activity of friedelin rich fraction (IND‐HE) separated from Cissus quadrangularis and its effect on female sexual function. PharmacognosyRes. 2010; 2: 138‐45.

Estrogen Deficiency

• Loss of ovarian estrogen leads to:• Vaginal dryness and atrophy, resulting in painful intercourse

• Diminished vaginal sensation, resulting in decreased pleasure during intercourse and difficulty achieving orgasm

• Chronic vaginal and/or bladder infections

**Topical lubricants are palliative, not preventative**

Chism LA. Overcoming resistance and barriers to the use of local estrogen therapy for the treatment of vaginal atrophy. IntJ Womens Health. 2012; 4: 551‐57.

Vaginal Dryness/Atrophy

• Vaginal estriol effectively treats dryness and atrophic changes and is not associated with endometrial hyperplasia.

• Vaginal estrogen alters the vaginal flora by maintaining adequate pH and prevents recurrent UTIs.

Raz R, StammWE. A controlled trial of intravaginal estriol in postmenopausal women with recurrent urinary tract infections. N Eng J Med. 1993; 329: 753‐56.Hustin J, Van der Eynde JP. Cytologic evaluation of the effect of various estrogens given in Post‐menopause. Acta Cytologica. 1977; 21: 225‐28.

Estriol • Vaginal Estriol Cream: 1‐2 mg in 1 gram of cream. Using finger or applicator or suppository and have patient insert 1 gram (1/4 teaspoon) of cream or suppository into the vagina.

• Start with every night for 2‐4 weeks, depending on the severity then decrease frequency prn

• Severe Atrophy: add testosterone… estriol 1mg and testosterone 0.125 mg combined in 1 gram of vaginal cream.

Rigg LA. Estrogen replacement therapy for atrophic vaginitis. Int J Fertil. 1986; 31(S3): 29‐34.

No Question of Safety

• Estriol:• Hundreds of thousands (millions?) of patients• Not one adverse event reported to FDA• Legal and appropriate under all pharmacy standards• Estriol has a USP monograph• Currently in phase III trials to treat MS• Used in Asia and Europe for years; well supported in literature

• Sold by Wyeth in Europe

Haldane J. Sex hormone treatments for multiple sclerosis. J OrthomolMed. 2012; 27: 87‐92.Head KA. Estriol: safety and efficacy. Alt Med Rev. 1998; 3: 101‐113.Klotter J. Bioidentical hormones, estriol and the FDA. Townsend Letter. 2009; 309: 26‐27.

Estriol Summation Statement

• Review of 150 articles included are those which show:• Oral and vaginal estriol is not associated with increased risk of breast cancer

• Estriol is safe for use in postmenopausal women previously treated for breast cancer

• Estriol prevents bone loss and increases bone mineral density in postmenopausal women

• Oral estriol does not cause endometrial changes in postmenopausal women

• Estriol is effective in the treatment of atrophic vaginitis• Estriol is safe and effective for the treatment of climacteric symptoms in post menopausal women

• Vaginal application of estriol is systemically absorbedBluemountainrx.com. Estriol summation statement. Available at: http://www.bluemountainrx.com/estriol.pdf. Accessibility verified November 7, 2012.

IND‐HE

• IND‐HE (friedelin rich fraction), a triterpenoid constituent of botanicals reported to have estrogenic activity

• Cissus quadrangularis• Cissus repens• Eleutherococcus


IND‐HE – Potential Treatment?

“IND‐HE exhibits mild to moderate estrogenic activity. Estrogen treatment increases excitability and reproductive behavior. Sexual behavior… showed remarkable similarity”


Estrogen Dominance

Estrogen dominance (progesterone insufficiency) is both 10 and 20 contributor to libido

Lee JR. Natural Progesterone: The Multiple Roles of a Remarkable Hormone. Sebastopol, CA: BLL Publishing; 1993.

Estrogen Dominance• Estrogen dominance refers to an excess of estrogen relative to progesterone

• Common in women of reproductive years, commonly present in PMS, menopause and with hormone replacement

• Over supplementation• Poor estrogen/progesterone balance

• Worsened by:• High estrogenic environment • Poor estrogen metabolism• Poor diet• Insulin resistance• Anovulation

John R Lee MD1929‐2003

Lee J. What Your Doctor Didn’t Tell You About Menopause: Balance Your Hormones and Your Life from Thirty to Fifty. New York, NY: Warner Books; 1999.

Progesterone vs. Progestin

Progesterone Medroxyprogesterone Acetate

References

• Fitzpatrick LA, et al. Comparison of regimens containing oral micronized progesterone or medroxyprogesterone acetate on quality of life in postmenopausal women: a cross‐sectional survey. J womens Health Gend Based Med. 2000; 9: 381‐387.

• Holtorf K. The bio‐identical hormone debate: are bio‐identical hormones (estradiol, estriol, progesterone) safer or more efficacious than commonly used synthetic versions in hormone replacement therapy? PostgradMed. 2009; 121: 1‐13.

• Fournier A, et al. Breast cancer risk in relation to different types of hormone replacement therapy in the E3N‐EPIC cohort. Int J Cancer. 2005; 114: 448‐54.

• Cummings JA, Brizendine L. Comparison of physical and emotional side effects of progesterone or medroxyprogesterone in early postmenopausal women. Menopause. 2002; 9: 253‐263.

• Lindenfeld EA, Langer RD. Bleeding patterns of the hormone replacement therapies in the postmenopausal estrogen and progestin interventions trial. Obstet Gynecol. 2002; 100.

• Murkes D, et al. Effects of percutaneous estradiol‐oral progesterone versus oral conjugated equine estrogens‐medroxyprogesterone acetate on breast cell proliferation and bcl‐2 protein in healthy women. Fertil Steril. 2011; 95: 1188‐91.

• Bernstein P, Pohost G. Progesterone, progestins and the heart. Rev Cardiovasc Med. 2010; 11: 228‐36.

Progesterone

• Mediates receptivity to partner approach• Directly plays a key role in maintaining libido (think progesterone surge at ovulation)

• Study of female hamsters with ovaries removed showed revival of sexual activity only after progesterone was added to estrogen therapy.


Estrogen dominance

Symptoms of estrogen dominance are 20 contributors to decreased libido:

• Irritability• Bloating• Depressed mood• Anxiety• Mood swings


Balancing with progesterone

• Dosage scheduling guidelines:• If pre‐menopausal:

• Interested in conception, use Pg days 14‐28 each cycle (during the luteal phase)

• NOT interested in conception, use Pg days 7‐28 (week of menses off)

• If peri‐menopausal, use Pg days 7‐28 (when not bleeding) each cycle

• If menopausal, treat continuously

Mead JH, Lommen ET. Slim Sane and Sexy: Pocket Guide to Natural, Bioidentical Hormone Balancing. Rancho Mirage, CA: Fountain of Youth Press; 2008.

Balancing with progesterone

Progesterone cream* starting dose 20‐60 mg QD (divided, BID dosing when vasomotor symptoms are present)• Dosage potency guidelines:

• For women weighing < 150lbs: 20‐30 mg topically qd• For women weighing > 150lbs: 40‐60 mg topically qd

*Topical progesterone is better absorbed than oral due to large first pass liver effect.

Adjust dosing based on patient’s response, metabolism and saliva hormone levels.

Mead JH, Lommen ET. Slim Sane and Sexy: Pocket Guide to Natural, BioidenticalHormone Balancing. Rancho Mirage, CA: Fountain of Youth Press; 2008.

Hypoandrogenism

Testosterone plays an essential role in female libido and, when elevated testosterone levels are not present, supplementation has been shown to be beneficial to increasing libido

Panay N, et al. Testosterone treatment of HSDD in naturally menopausal women: the ADORE study. Climacteric. 2010; 13: 121‐31.Mead JH, Lommen ET. Slim Sane and Sexy: Pocket Guide to Natural, Bioidentical Hormone Balancing. Rancho Mirage, CA: Fountain of Youth Press; 2008.

Testosterone

Adequate testosterone contributes to libido and desire, arousal, frequency, satisfaction and decreased vaginal dryness

Decreased testosterone levels most commonly associated with:

• Age• Oophorectomy • Oral estrogens

Bolour S, Braunstein G. Testosterone therapy in women: a review. Int J Impot Res. 2005 Sep‐Oct; 17(5): 399‐408.

Testosterone

“Based on evidence of current studies, it is reasonable to consider testosterone therapy for a symptomatic androgen‐deficientwoman with women’s sexual interest and desire disorder.”

Bolour S, Braunstein G. Testosterone therapy in women: a review. Int J Impot Res. 2005 Sep‐Oct; 17(5): 399‐408.Panay N, et al. Testosterone treatment of HSDD in naturally menopausal women: the ADORE study. Climacteric. 2010; 13: 121‐31.

Testosterone

• Off‐label use of testosterone, typically in women over 40 y.o.

• Transdermal patches and topical gels preferred route of delivery to avoid first‐pass metabolism (hepatotoxic)

• Typical transdermal dosing is .5‐1.5 mg QD

Bolour S, Braunstein G. Testosterone therapy in women: a review. Int J Impot Res. 2005 Sep‐Oct; 17(5): 399‐408.Hubayter Z, Simon JA. Testosterone therapy for sexual dysfunction in postmenopausal women. Climacteric. 2008 Jun; 11 (3): 181‐91.

Beyond Testosterone

“Less than half of women recover libido through testosterone therapy”

Mead JH, Lommen ET. Slim Sane and Sexy: Pocket Guide to Natural, Bioidentical Hormone Balancing. Rancho Mirage, CA: Fountain of Youth Press; 2008.

“Less than half of women recover libido through testosterone therapy”

Dehydroepiandrosterone (DHEA)

Physiological decline with age, beginning in the 3rd decade• 80% decrease in DHEA by age 70

Often overlooked in clinical practice. However, clinical results may support use in women with low testosterone, as DHEA is a hormonal precursor to testosterone

Fonesca HP, et al. Androgen deficiency in women. Rev Assoc Med Bras. 2010; 56: 579‐82.University of Maryland Medical Center. Dehydroepiandrosterone. Available at: http://www.umm.edu/altmed/articles/dehydroepiandrosterone‐000299.htm. Accessibility verified November 1, 2012.

DHEA

216 postmenopausal women with moderate to severe vaginal atrophy using 10 mg PV QD x 12 weeks reported:• 49% and 23% improvement of desire domain• 68% improvement in arousal/sensation• 39% improvement in arousal/lubrication• 75% improvement in orgasm• 57% improvement in dryness during intercourseUsing the Menopause Specific Quality of Life and Abbreviated Sex Function questionnaires

Labrie F. Effect of intravaginaldehydroepiandrosterone (Prasterone) on libido and sexual dysfunction in postmenopausal women. Menopause. 2009; 16: 923‐31.

DHEA supplementation

• Can be oral or topical• Oral start with 5‐15 mg Q AM• Topical 5 to 10 mg Q AM

• Pro‐hormone, converts to testosterone and estrogen in both men and women

• Be careful with supplementation with overweight women—can elevate estrogen levels significantly

Mead JH, Lommen ET. Slim, Sane & Sexy: Pocket Guide to Natural, Bioidentical Hormone Balancing. Rancho Mirage, CA: Fountain of Youth Press: 2009.

Hyperandrogenism

Evolving/established insulin resistance in women can result in elevated androgens (DHEA and/or testosterone) without a direct increase in libido.

Speroff L. Clinical Gynecologic Endocrinology and Infertility. Philadelphia, PA: Lippincott Williams & Wilkins; 2005.Chedraui P, Pérez‐López FR, Blümel JE, Hidalgo L, Barriga J.. Hyperglycemia in postmenopausal women screened for the metabolic syndrome is associated to increased sexual complaints. Gynecol Endocrinol. 2010 Feb;26(2):86‐92.

Testosterone and female sexual function

A study of 106 women who underwent bariatric surgery demonstrated significant improvement in overall sexual functioning and a decrease in total testosterone from baseline at years 1 and 2 postoperatively.

Sawyer D, Sptizer J, Watten T, et al. Changes in sexual functioning and sex hormone levels in women following bariatric surgery. JAMA Surg; Nov 4 2013

Stress and sex

Stress has been found to be negatively associated with sexual function.

Physiologically mediated by the adrenal glands, chronic stress leads to decreased cortisol output.

Wallwiener CW, et al. Prevalence of sexual dysfunction and impact of contraception in female German medical students. J Sex Med. 2010; 7: 2139‐48.Hsieh YH, et al. The levels of stress and depression among interns and clerks in three medical centers in Taiwan—a cross‐sectional study. Chang Gung Med J. 2011; 34: 278‐85.

Distress About Sex

“The best predictors of sexual distress were markers of general emotional well‐being and emotional relationship with the partner during sexual activity.”

Bancroft MD, Loftus J, MA, Long J.S., PhD. Distress About Sex: A National Survey of Women in Heterosexual Relationships. Archives of Sexual Behavior, Vol 32, No 3, June 2003 pp 193‐208

Additional Botanical and Nutraceutical Considerations

Addition of botanical support and nutraceuticals• Maca – support stamina, energy and sexual function• Damiana – promote relaxation • Korean ginseng – upregulate NO activity, increase NO production in endothelial cells. May promote relaxation of clitoral cavernosal mm and vaginal smooth mm

• Ginko biloba – promote microvascular circulation• Sea Buckthorn – support vaginal tissue moisture• L‐arginine – increase NO for vasodilation and arousal

Ito TY, et al. The enhancement of female sexual function with ArginMax, a nutritional supplement, among women differing in menopausal status. J Sex Marital Ther. 2006; 34: 369‐78.

Korean red ginseng (KRG)

32 menopausal women in a placebo‐controlled, double‐blind, crossover clinical study received placebo or 1 gm KRG PO QD.

Results: Significant improvement in FSFT and GAQ scores. “Oral administration of KRG extracts improved sexual arousal in menopausal women.”

*2 cases of vaginal bleeding were reported during KRG treatment

Oh KJ, et al. Effects of Korean red ginseng on sexual arousal in menopausal women: placebo‐controlled, double‐blind crossover clinical study. J Sex Med. 2010; 7: 1469‐77.

Pharmaceutical options?Pharmaceutical options are sparse (likely because female sexual dysfunction is multifactorial and, thus treatment is as well)

• Sildenafil• Off‐label use for arousal disorders have been used without consistently positive results

• Topical sensation creams• Can be ordered through compounding pharmacy and often contain vasodilator (arginine) and sensitizing agents (menthol)

Basson R. et al. Efficacy and safety of sildenafil citrate in women with sexual dysfunction associated with female sexual arousal disorder. J WomensHealth Gend Based Med. 2002; 11: 367‐77.Leddy LS, et al. Influence of Sildenafil on genital engorgement in women with female sexual arousal disorder. J Sex Med. 2012; 9: 2693‐97.

More Than Just Hormones….

Neurotransmitters

• Neurotransmitters are responsible for regulating aspects of mood, cognition and behavior including:

• Sexual motivation• Reward seeking

Georgiadis JR, KringelbachML. The human sexual response cycle: Brain imaging evidence linking sex to other pleasures. Prog Neurobiol. 2012; 98: 49‐81.

Neurotransmitters

• Excitatory or inhibitory in nature: • Excitatory components stimulate sexual desire• Inhibitory components stimulate sexual reward, sedation and satiety

Pfaus JG. Pathways of sexual desire. J Sex Med. 2009; 6: 1506‐33.

Neurotransmitters

Decreased libido may be due to:Reduced excitatory activity

and/orIncreased inhibitory activity

Pfaus JG. Pathways of sexual desire. J Sex Med. 2009; 6: 1506‐33.

Neurotransmitters

Excitatory: • Dopamine • Norepinephrine and Epinephrine • Glutamate

Desire requires balance of inhibitory and excitatory factors

Clayton AH. The pathophysiology of hypoactive sexual desire disorder in women. Int J GynaecolObstet. 2010; 110: 7‐11.Anderson KE. Pharmacology of Penile Erection. Pharmacological Reviews Sep 1 2000; 53(3) 417‐450.

Inhibitory: • GABA

Excitatory OR Inhibitory:• Serotonin (dependent on amount and receptor subtype)

Dopamine• Essential for desire and subjective sense of arousal• Assists in modulation of arterial blood flow and

mediation of erection

Clayton AH. The pathophysiology of hypoactive sexual desire disorder in women. Int J GynaecolObstet. 2010; 110: 7‐11.Andersson KE. Pharmacology of Penile Erection. Pharmacological Reviews Sep 1 2000; 53(3) 417‐450.

Norepinephrine and Epinephrine

• Essential for regulating arousal• Increase of levels until peak at orgasm, with rapid decline thereafter

• Critical in regulation of vasoconstriction/relaxation of the corpora cavernosa

Clayton AH. The pathophysiology of hypoactive sexual desire disorder in women. Int J GynaecolObstet. 2010; 110: 7‐11.Simon JA. Low sexual desire – is it all in her head? Pathophysiology, diagnosis and treatment of hypoactive sexual desire disorder. PostgradMed. 2010; 112: 128‐36Kruger TH, Haake P, Chereath D et al. Specificity of the neuroendocrine response to orgasm during sexual arousal in men. J Endocrinol. 2003 Apr; 177(1): 57‐64Saenz de Tejada L, Kim NN, Goldstein L, Traish AM. Regulation of pre‐synaptic alpha adrenergic activity in the corpus cavernosum. Int J Impot Res. 2000 Mar; 12 Suppl 1:S20‐25

Norepinephrine and Epinephrine

Proper conversion of NE E requires magnesium, SAMe and cortisol

Folling, A. By excretion of urinary phenylpyruvic in as a metabolic anomaly in connection with imbecility.Physiol. Chem. 227: 169‐176. 1934

Supporting D/NE/E

Dopamine, norepinephrine and epinephrine may be depleted due to stress. Low to low‐range levels may be boosted with: • Tyrosine: precursor amino acid

• 50‐1,500 mg qd• Mucuna pruriens: bean contains 3% – 6% L‐dopa

• 200‐800 mg qd

Raghavendra S, et al. Enhanced production of L‐DOPA in cell cultures of Mucuna pruriens L. and Mucuna prurita H. Nat Prod Res. 2010; 26: 729‐801.An alternative medicine treatment for Parkinson’s disease: Results of a multicenter clinical trial. J Alt Comp Med. 1995; 1: 249‐55.InfanteME, et al. Outbreak of acute toxic psychosis attributed to Mucuna pruriens. Lancet. 1990; 336: 1129.Neri DF, et al. The effects of tyrosine on cognitive performance during extended wakefulness. Aviat Space Environ Med. 1995; 66: 313‐19.National Academy Press. The Role of Protein and Amino Acids in Sustaining and Enhancing Performance. Available at: http://www.nap.edu/openbook.php?record_id=9620&page=R1 . Accessibility verified November 1, 2012.

Serotonin

• Modulator of central neuroregulatory control of penile erection

• Role in initiation of sexual arousal • Affects vascular tone and blood flow• Facilitates uterine contractions, thus affecting female orgasm

Simon JA. Low sexual desire – is it all in her head? Pathophysiology, diagnosis and treatment of hypoactive sexual desire disorder. Postgrad Med. 2010; 112: 128‐36. Frohilch PF, Meston CM. Evidence that serotonin affects female sexual functioning via peripheral mechanisms. Physiology & Behavior . 2011 71(2000) 383‐393Andersson KE. Pharmacology of Penile Erection. Pharmacological Reviews Sep 1 2000; 53(3) 417‐450.

Serotonin

• May interfere with sexual function by:

• Reducing sensation• Reducing adrenergic effects• Inhibiting NO synthase• Stimulating 5‐HT receptors, thus inhibiting orgasm (SSRI sexual dysfunction)

Simon JA. Low sexual desire – is it all in her head? Pathophysiology, diagnosis and treatment of hypoactive sexual desire disorder. PostgradMed. 2010; 112: 128‐36.

Maca

“Peru’s Natural Viagra?”A study of 17 women, ages 23‐49, found 3.0 g Maca root PO QD to be beneficial in alleviating SSRI‐induced sexual dysfunction, suggesting beneficial effect to libido.

Dording CM, et al. A double‐blind, randomized, plot dose‐finding study of maca root (L. meyenii) for the management of SSRI‐induced sexual dysfunction. CNS Neurosci Ther. 2008; 14: 182‐91.

Yohimbe

• An evergreen tree found in Zaire, Cameroon and Gabon, the bark is used to make yohimbine, available by prescription.

• An alpha‐2‐adrenergic antagonist and weak MAO inhibitor, may be effective at reversing sexual side effects associated with SSRIs (for both men and women)

• May be effective for erectile dysfunction not associated with SSRIs

Saenz de Tejada L, Kim NN, Goldstein L, Traish AM. Regulation of pre‐synaptic alpha adrenergic activity in the corpus cavernosum. Int J Impot Res. 2000 Mar; 12 Suppl 1:S20‐25Ernst E, PittlerMH. Yohimbine for erectile dysfunction: a systemic review and meta‐analysis of randomized clinical trials. J Urol. 1998 Feb:159(2):433‐6

Supporting Serotonin

• Decreased serotonin levels may be supported with: • L‐tryptophan: 500‐2000 mg QD• 5 HTP supplementation: 50 mg‐600 mg QD

• Supporting elevated serotonin levels: • L‐theanine 10‐500 mg BID

Nakajima T, et al. Clinical evaluation of 5‐hydroxy‐L‐tryptophan as an antidepressant drug. Folia Psychiatr Neurol Jpn. 1978; 32: 223‐30.PoldingerW, et al. A functional‐dimensional approach to depression: serotonin deficiency as a target syndrome in a comparison of 5‐hydroxytryptophan and fluvoxamine. Psychopathology. 1991; 24: 53‐81.Self Nutrition Data. Foods highest in tryptophan. Available at: http://nutritiondata.self.com/foods‐000079000000000000000.html . Accessibility verified October 31, 2012.

Assessing Sexual Dysfunction

• Query and rule out: lifestyle/psychosocial/physiological factors

• Pertinent physical exams• Salivary hormone testing: E2, prog, test, DHEA, C x 4

• Serum testing: CBC, CMP, lipids, TSH, FT3 FT4, ferritin• Urinary neurotransmitter levels: dopamine, norepi, epi, serotonin, GABA, glutamate

Marc DT, Ailts JW, Campeau DC, Bull MJ, Olson KL.. Neurotransmitters excreted in the urine as biomarkers of nervous system activity: validity and clinical applicability. Neurosci BiobehavRev. 2011 Jan;35(3):635‐44. Epub 2010 Aug 7.GozanskyWS, et al. Salivary Cortisol Determined by Enzyme Immunoassay is Preferable to Serum Total Cortisol for Assessment of Dynamic Hypothalamic‐Pituitary‐Adrenal Axis Activity. Clin Endocrin (2005) 63:336‐341.

Communication Gap

• Only 35% of providers take a sexual history at least 75% of the time!

• 58% of women reported initiating the doctor‐patient conversation regarding sexual concerns!

• Only 22% of women over 50 talked to their doctor about sex!

Duthie EH, Katz PR, Malone M. Practice of Geriatrics. 4th ed. Philadelphia, PA: Saunders; 2007.Bachmann G. Female sexuality and sexual dysfunction: are we stuck on the learning curve? J Sex Med. 2006; 3: 639‐34.

Why the gap?

• Time constraints• Does not pertain to chief complaint• Provider feels uncomfortable• Provider has limited knowledge/training• Provider has limited treatment options

Neurosci Biobehav Rev. 2011 Jan;35(3):635‐44. Epub 2010 Aug 7.

Closing the Gap

• Utilize sexual health questionnaires as part of the intake or assessment

• Female Sexual Function Index (female only)• Sexual Distress Scale (male and female)• Decreased Sexual Desire Screener (female only)

• Ask direct questions• Listen respectfully• Routinely make sexual health questions part of intake

Bachmann G. Female sexuality and sexual dysfunction: are we stuck on the learning curve? J Sex Med. 2006; 3: 639‐34.

Closing the Gap

Sample questions:• “Do you have any sexual health concerns today?”

• “Many women going through menopause experience symptoms like decreased sex drive, pain with intercourse or vaginal dryness. Are any of these a concern for you?”

Treating Sexual DysfunctionUse a comprehensive interview, exam and lab work to:1) Lay a strong foundation:

• Individualized hormone balancing via BHRT• Address neurotransmitter imbalances

Ahmad MK, et al. Withania somnifera improves semen quality by regulating reproductive hormone levels and oxidative stress in seminal plasma of infertile males. Fertil Steril. 2010; 94: 989‐96.

Treating Sexual Dysfunction

2) Treat underlying physiological conditions3) Address lifestyle contributors:

• Lifestyle modification• Medication changes, substance use, sleep hygiene• Making intimacy a priority – date night, timing of intimacy, involve partner & create excitement

4) Address psychosocial contributors:• Encourage positive self‐talk & self‐image• Teach stress management, mindfulness

• Enlist the help of a therapist

Summary

Sexual dysfunction is a prevalent concern among both men and women across all age groups, influencing quality of life and stemming from a multitude of factors including and often extending beyond testosterone.

Successful treatment of these concerns requires addressing multiple factors (lifestyle, underlying medical problems, psychosocial concerns) while laying a strong foundation via individualized hormone and neurotransmitter balancing.

sexual vitality: it’s all about chemistry · report experiencing sexual dysfunction at some point...

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