Introduction to Women’s Health-- Script

Slide 1 Good morning! I am Dr. Becky Haak and today begins your foray in to the world of Women’s Health. I graduated from IU School of Medicine in 1982. Went into a family practice residency then switched to OB-GYN. I’ve been in private practice for 23 years, doing only gynecology for the past 7.

The rest of your lectures in this series will focus on female reproduction and diseases of the reproductive tract. Before delving into those areas, I’d like to take this time to step back and focus on the larger ways in which gender impacts health and disease, specifically through FORM, Function, and Foundations. There will be 3 test questions from this lecture but if you’ll follow the flow of the lecture, I think you won’t need lots of notes to get the points.

During this presentation, there are 3 short interviews with community based doctors of different specialties addressing gender specific Form and Function as it relates to their daily practice.

Slide 2 FORM = Anatomy Male and female anatomy differ in several areas. RIght now we’re going to think about the differences in the urogenital tract, specifically urethral length, urethral position, the support of the pelvic floor and continence mechnisms (what keeps urine in the bladder and not running down our legs).

Slide 3 In this newborn baby girl, the length of the urethra is about 1 cm or the width of my fingernail. The length of a baby boy’s urethral is 3-4 cm, the length of my finger. The anatomy has implications for frequency of UTI’s and ureteral reflux

Slide 4 Dr. Christine Bender Pediatrics

Slide 5 Urethral length, the position of the urethra in relationship to the rectum- these are specific anatomy differences leading to more UTI’s with the possibility of long term kidney damage. BUt what about other anatomic issues over the course of a lifetime?

Slide 6 With adolescence comes the production of sex steroids. THe increase in estrogen causes thickening of the vaginal epithelium. THis slide shows a healthy vaginal epithelium with lots of blood vessels below the surface, a thick intermediate layer above the basalis, and lots of superficial cells filled with glycogen.

Slide 7 At menopause, estrogen levels decline and that thick, lush vaginal epithelium reverses. On the Right is the vaginal histology with estrogen as previously described. On the left is vaginal epithelium without estrogen- much less blood supply underneath, less collagen, less elasticity, and only a few parabasal cells on top of the basement membrane. Women complain of vaginal dryness and may have bleeding after intercourse from disruption of this skin.

Slide 8 Back to adolescence, the reproductive organs hypertrophy and mature. The striated muscles and connective tissue in the pelvic floor support these organs as well as supporting the bladder and rectum.

Slide 9 During pregnancy, the growing baby and uterus, exert ongoing and increasing pressure against the pelvic floor. With vaginal delivery, there can be permanent damage to these supportive muscles and ligaments, their attachments to the pelvis, and to the nerve supply to the pelvis.

Slide 10 Over the course of a lifetime, anything that increases abdominal pressure can further weaken this pelvic floor support mechanism. More babies, lifting, carrying, obesity, and just gravity over time cause increased issues.

Slide 11 When these pelvic floor support mechanisms are damaged and the elasticity wanes without estrogen, disorders of the pelvic floor occur. IF the urethra is no longer up behind the symphysis there may be loss of urine with even mild physical activity. THis is called STRESS INcontinence. WIth the decrease in elasticity after menopause, the bladder may not tolerate being full of urine and suddenly contract with little warning leading to URGENCY incontinence. This is a dynamic MRI showing the descent of pelvic structures caused by straining in a woman with a disorder of her pelvic floor.

Slide 12 In the worst case scenarios, the entire pelvic floor support mechanism fails and the pelvic organs are on the outside- not inside. THis shows what that looks like.

Slide 13 Dr Ronald Suh Urologist

Slide 14 From birth to senescence, gender specific anatomy alters health and disease.

Slide 15 Now let’s talk about FUNCTION. The way our bodies function, i.e. Physiology, is also altered by gender.

Slide 16 In 1991, Dr. Bernadine Healy was appointed by President BUsh to be director of the National Institutes of health. Dr. Healy is a well-respected cardiologist and was the first female director of NIH. As her first move, she initiated a large , nation-wide project called “The WOmen’s Health INitiative.” WHI involved 161,000 women ages 50-79, over 15 years. It’s goal was to develop prevention strategies for heart disease, breast & colon cancer, as well as osteoporotic fractures in women.

Slide 17 The #1 cause of death in women is cardiovascular disease. Yet in 1991, when WHI started, research in heart disease had been conducted almost exclusively on men. Now that doesn’t seem like a big deal - after all a heart is a heart- but there are gender differences in heart disease.

Slide 18 At that time, we were well aware that heart disease in women develops later than in men. Actually, it’s not until after menopause that the incidence of heart disease in women begins to match our male counterparts. For that reason, the assumption was that our hormones protected our hearts. In 1996, this pamphlet was issued from the American College of

Obstetricians and Gynecologists to educate patients on the benefits of hormone replacement therapy, including ‘Protection from Cardiovascular Disease.’

Slide #19 Dr. Robert Glassman

Slide #20 While we were excited about positive impact of estrogen on HDL, we’d sort of overlooked the negative impact on clotting. Remember this clotting cascade? Production of a lot of these clotting cofactors in the liver is increased by estrogen. It also appears to decrease production of Anti-Thrombin III.

Slide #21 Subsequently, in a vessel like this, where the flow is disrupted by a plaque, a clot is more likely to form.

Slide # 22 And indeed, when the data started flowing out of the WHI, it became clear that post menopausal hormone replacement therapy didn’t protect women from MI, and actually increased the risk in the first year of taking it. This article is from the NEJM 2003 from the WHI investigators.

Slide #23 So how does gender impact cardiovascular disease, in particular MI? Only 50% of women have classic chest pain as their presenting symptom. On average we’re 10 yr older with our first MI, but more likely to die with it than a man. If we survive, we’re more prone to Congestive Heart failure. The cause of our MI will probably be MICROvascular disease- disease in the small arteries of the heart- not MACULARvascular dx, more common in men. Subsequently, the abnormalities may be less likely to show up on conventional angiography and our outcomes may not be as good with standard treatments such as stents and bypass grafts.

Slide #24 FUNCTION Thanks in part to Dr. Healy and the Women’s Health Initiative, we’re more aware that estrogen and it’s impact on physiology is not just a reproductive issue.

Slide #25 Last but certainly not least, Gender affects health and disease at our very foundations- the cell.

Slide #26 Hormones exert their actions on specific target tissues through cellular receptors. The response to that hormone is specific to the receptor and the cell in which it resides.

Slide #27 Let’s take a minute to get a peek at some pharmacology you’re not yet learned. Today’s story is about tamoxiphen.

Slide #28 70-80% of breast cancers abnormally express hormone receptors on their cells. When that hormone sits in that cancer cell receptor, the cells abnormally proliferate- like a turn on switch for abnormal growth. If we had a hormone look-alike that would sit in that receptor and NOT turn on the growth, perhaps we could “shut off the on-switch” so to speak. And indeed in the 1970’s, such a molecule was produced. It’s name is Tamoxiphen and it modulates the estrogen receptor in the breast by sitting in the receptor and doing NOTHING. Thus the name

SERM- or Selective estrogen receptor modulator. This has been a great move forward in treating estrogen-receptor + breast cancers and is currently used for that purpose.

Slide #29 When Tamoxiphen was developed and an Anti-estrogen for tx in breast cancer, we thought all estrogen receptors would work the same. Not so. Endometrial cancers began to pop up in patients on Tamoxiphen. It turns out that while BLOCKING the estrogen receptors in the breast, it seems to STIMULATE the receptors in the endometrium. Bummer.

However, the risk of endometrial cancer is small with tamoxiphen use and easily treated with hysterectomy, subsequently it is still very useful for breast cancer treatment, but this new knowledge about estrogen receptors opened the door for other developments.

Slide #30 In the late 1980’s our neighbors down the street were looking for a better Estrogen Receptor Modulator and found Raloxiphen ( a very similar molecule). Now we have a SERM that helps in the breast, (though not as much as Tamoxiphen) , doesn’t stimulate the endometrium to cause endometrial cancer, but the biggest news wwas the effect it has on bones.

Without estrogen, osteoclastic cells in the bone take over. These cells break down bone. The osteoblastic cells which build bone diminish in activity. The result is declining bone mass.

Slide # 31 With a loss in the density of the bone, fractures especially of the spine and hip become increasingly common. In fact it is So common that 1 out of every 2 women will experience an osteoporotic fracture at some time in their life.

In 1993, the FDA approved Raloxiphen for use in treating and preventing osteoporosis. Now we have a way to modulate the cellular estrogen receptors to BLOCK proliferation of breast cancer cells with estrogen receptors, and stimulate estrogen receptors on bone to decrease osteoporotic fractures. Cool.

Slide #32 Now things are moving. Where else are there estrogen receptors we could modulate to ameliorate disease?

Around 2000, estrogen receptors were found in the eye. Is that why there are differences in male/female incidence of macular degeneration- the leading cause of blindness in aging?What about the estrogen receptors in the brain? Why does estrogen have an impact on colon cancer (another finding from WHI data) ? Lupus occurs in women at a ratio of 9:1- almost exclusively before menopause. Does estrogen have a part in that story?

Slide #33 From 2000 to 2010,numerous articles have been published exploring the many ways sex steroids alter our bodies at the cellular level. This is the new frontier in women’s health.

Slide #34 To wrap it up, there are gender specific anatomic differences in FORM which affect our susceptibility to pathology.

Our hormones alter our physiology, impacting FUNCTION of both reproductive and non-reproductive organ systems.

There are fundamental differences in cellular receptors and the hormones that manipulate them, which may provide opportunities to alter disease at the FOUNDATIONS- the cells themselves. Thanks for your attention