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12.1: Case Study- Hormones and Health - Biology

12.1: Case Study- Hormones and Health - Biology


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Case Study: Hormonal Havoc

18-year-old Gabrielle checks her calendar. It has been 42 days since her last menstrual period, two weeks later than the length of the average woman’s menstrual cycle. Although many women would suspect pregnancy if their period was late, Gabrielle has not been sexually active. She is not even sure she is “late” because her period has never been regular. Ever since her first period at 13 years of age, her cycle lengths have varied greatly, and there are months where she does not get a period at all. Her mother told her that a girl’s period is often irregular when it first starts, but Gabrielle’s still has not become regular five years later. She decides to go to the student health center on her college campus to get it checked out.

The doctor asks her about the timing of her menstrual periods and performs a pelvic exam. She also notices that Gabrielle is overweight, has acne, and excess facial hair. As she explains to Gabrielle, while these physical characteristics can be perfectly normal, in combination with an irregular period they can be signs of a disorder of the endocrine, or hormonal, system called polycystic ovary syndrome (PCOS).

In order to check for PCOS, the doctor refers Gabrielle for a pelvic ultrasound and sends her to the lab to get blood work done. When her lab results come back, Gabrielle learns that her levels of androgens (a group of hormones) are high, and so is her blood glucose (sugar). The ultrasound showed that she has multiple fluid-filled sacs known as cysts in her ovaries. Based on Gabrielle’s symptoms and test results, the doctor tells her that she does indeed have PCOS.

PCOS is common in young women. It is estimated that between 1 in 10 to 20 women of childbearing age have PCOS — as many as five million women in the United States. You may know someone with PCOS or may have it yourself.

Read the rest of this chapter to learn about the glands and hormones of the endocrine system, their functions, how they are regulated, and the disorders ­­— such as PCOS ­­— that can arise when hormones are not regulated properly. At the end of the chapter, you will learn more about PCOS, its possible long-term consequences including fertility problems and diabetes, and how these negative outcomes can sometimes be prevented with lifestyle changes and medications.

Chapter Overview: Endocrine System

In this chapter, you will learn about the endocrine system, a system of glands that secrete hormones that regulate many of the body’s functions. Specifically, you will learn about:

  • The glands that make up the endocrine system and how hormones act as chemical messengers in the body.
  • The general types of endocrine system disorders.
  • The types of endocrine hormones, including steroid hormones such as sex hormones, and non-steroid hormones such as insulin; and how they affect the functions of their target cells by binding to different types of receptor proteins.
  • How the levels of hormones are regulated mostly through negative, but sometimes through positive, feedback loops.
  • The master gland of the endocrine system, the pituitary gland, controls other parts of the endocrine system through the hormones that it secretes; and how the pituitary itself is regulated by hormones secreted from the hypothalamus of the brain.
  • The thyroid gland and its hormones, which regulate processes such as metabolism and calcium homeostasis; how the thyroid is regulated; and the disorders that can occur when there are problems in thyroid hormone regulation, such as hyperthyroidism and hypothyroidism.
  • The adrenal glands, which secrete hormones that regulate processes such as metabolism, electrolyte balance, responses to stress, and reproductive functions; and the disorders that can occur when there are problems in adrenal hormone regulation, such as Cushing’s syndrome and Addison’s disease.
  • The pancreas, which secretes hormones that regulate blood glucose levels such as insulin; and disorders of the pancreas and its hormones including diabetes.

As you read this chapter, think about the following questions:

  1. Why can hormones have such a broad-range effect on the body, such as is seen in PCOS?
  2. Which hormones normally regulate blood glucose and how is this related to diabetes?
  3. What are androgens? How do you think their functions relate to some of the symptoms that Gabrielle is experiencing?

Aiko, 22, and Larissa, 23, met through mutual friends and hit it off right away. They began dating and just four months later, they are now madly in love. They spend as much time as they can with each other, and have decided to move in together when Larissa’s roommate moves out. They are even discussing getting married one day.

Inspired by his passion for Larissa, Aiko is considering getting her name tattooed on his arm. As you probably know, tattoos are designs on the skin created by injecting pigments into the skin with a needle. Aiko looks up different tattoo styles online, and starts to envision what he would want in a tattoo.

One day at a street festival, Aiko sees a sign that says “Henna Tattoos.” Henna tattoos are not technically tattoos — they are temporary designs that artists can create on the skin using a paste made out of the leaves of the henna plant. The henna stains the skin a reddish-brown colour, and once the paste is scraped off, the design typically remains on the skin for a few weeks. The use of henna to create designs on the skin is called mehndi. It is traditionally used by people in and from regions such as India, Pakistan, the Middle East, and Africa to celebrate special occasions, particularly weddings. Mendhi is often done on the palms of the hands and soles of the feet, where the designs usually come out darker than on other areas of the skin. You can see some examples of henna art in the images below.

Figure 10.1.2 Examples of henna art.

Aiko asks the mehndi artist to inscribe Larissa’s name on his arm, so that he can see whether he likes it without making the permanent commitment of a real tattoo. Two days later, Aiko visits his parents. They are not familiar with mehndi, and they have a moment of panic when they think he got a real tattoo. Aiko reassures them that it is temporary, but tells them that he is thinking about getting a real tattoo.

His parents are concerned. His father points out that he has not known Larissa long — what if they break up and he regrets the tattoo? His mother additionally worries about whether tattoos are safe. Aiko says that he doesn’t think he will regret the decision, but if he does, he can cover it up with another tattoo or get it removed with laser treatments. He also tells them that he would go to an artist and shop that are reputable, and take appropriate safety precautions. His parents warn him that getting a tattoo removed may not be as simple as he thinks, and that he should think very carefully before making such a permanent decision.

Humans have long decorated and adorned their skin with tattoos, makeup, and piercings. They also colour, cut, straighten, curl, and remove their hair and paint, grow, and cut their nails. The skin, hair, and nails make up the integumentary system. As you read this chapter, you will learn about the important biological functions that these organs carry out, beyond being a convenient canvas for personal expression. At the end of the chapter you will find out if Aiko got his tattoo. You will also learn more about how tattoos, mehndi, and laser tattoo removal work, as well as the important considerations to protect your health if you are thinking about getting a tattoo.


Chapter 18 Summary

In this chapter, you learned about the male and female reproductive systems. Specifically, you learned that:

  • The reproductive system is the human organ system responsible for the production and fertilization of gametes and, in females, the carrying of a fetus .
  • Both male and female reproductive systems have organs called gonads ( testes in males, ovaries in females) that produce gametes ( sperm or ova ) and sex hormones (such as testosterone in males and estrogen in females). Sex hormones are endocrine hormones that control prenatal development of sex organs, sexual maturation at puberty , and reproduction after puberty.
  • The reproductive system is the only organ system that is significantly different between males and females. A Y-chromosome gene called SRY is responsible for undifferentiated embryonic tissues developing into a male reproductive system. Without a Y chromosome, the undifferentiated embryonic tissues develop into a female reproductive system.
  • Male and female reproductive systems are different at birth, but immature and nonfunctioning. Maturation of the reproductive system occurs during puberty when hormones from the hypothalamus and pituitary gland stimulate the gonads to produce sex hormones again. The sex hormones, in turn, cause the physical changes experienced during puberty.
  • Male reproductive system organs include the testes, epididymis , penis , vas deferens , prostate gland , and seminal vesicles .
    • The two testes are sperm- and testosterone-producing male gonads. They are contained within the scrotum , a pouch that hangs down behind the penis. The testes are filled with hundreds of tiny, tightly coiled seminiferous tubules, where sperm are produced. The tubules contain sperm in different stages of development, as well as Sertoli cells, which secrete substances needed for sperm production. Between the tubules are Leydig cells , which secrete testosterone.
    • The two epididymides are contained within the scrotum. Each epididymis is a tightly coiled tubule where sperm mature and are stored until they leave the body during an ejaculation .
    • The two vas deferens are long, thin tubes that run from the scrotum up into the pelvic cavity . During ejaculation, each vas deferens carries sperm from one of the epididymides to one of the pair of ejaculatory ducts.
    • The two seminal vesicles are glands within the pelvis that secrete fluid through ducts into the junction of each vas deferens and ejaculatory duct. This alkaline fluid makes up about 70% of semen, the sperm-containing fluid that leaves the penis during ejaculation. Semen contains substances and nutrients that sperm need to survive and “swim” in the female reproductive tract.
    • The prostate gland is located just below the seminal vesicles and surrounds the urethra and its junction with the ejaculatory ducts. The prostate secretes an alkaline fluid that makes up close to 30% of semen. Prostate fluid contains a high concentration of zinc, which sperm need to be healthy and motile.
    • The ejaculatory ducts form where the vas deferens joins with the ducts of the seminal vesicles in the prostate gland. They connect the vas deferens with the urethra. The ejaculatory ducts carry sperm from the vas deferens, and secretions from the seminal vesicles and prostate gland that together form semen.
    • The paired bulbourethral glands are located just below the prostate gland. They secrete a tiny amount of fluid into semen. The secretions help lubricate the urethra and neutralize any acidic urine it may contain.
    • The penis is the external male organ that has the reproductive function of intromission , which is delivering sperm to the female reproductive tract. The penis also serves as the organ that excretes urine. The urethra passes through the penis and carries urine or semen out of the body. Internally, the penis consists largely of columns of spongy tissue that can fill with blood and make the penis stiff and erect. This is necessary for sexual intercourse so intromission can occur.
      • Spermatogenesis occurs in the seminiferous tubules in the testes, and requires high concentrations of testosterone. Sertoli cells in the testes play many roles in spermatogenesis, including concentrating testosterone under the influence of follicle stimulating hormone (FSH) from the pituitary gland.
      • Spermatogenesis begins with a diploid stem cell called a spermatogonium , which undergoes mitosis to produce a primary spermatocyte. The primary spermatocyte undergoes meiosis I to produce haploid secondary spermatocytes, and these cells in turn, undergo meiosis II to produce spermatids. After the spermatids grow a tail and undergo other changes, they become sperm.
      • Before sperm are able to “swim,” they must mature in the epididymis. The mature sperm are then stored in the epididymis until ejaculation occurs.
        • ED is a disorder characterized by the regular and repeated inability of a sexually mature male to obtain and maintain an erection. ED is a common disorder that occurs when normal blood flow to the penis is disturbed or there are problems with the nervous control of penile engorgement or arousal.
            • Possible physiological causes of ED include aging, illness, drug use, tobacco smoking, and obesity, among others. Possible psychological causes of ED include stress, performance anxiety, and mental disorders.
            • Treatments for ED may include lifestyle changes, such as stopping smoking and adopting a healthier diet and regular exercise. However, the first-line treatment is prescription drugs such as Viagra® or Cialis® that increase blood flow to the penis. Vacuum pumps or penile implants may be used to treat ED if other types of treatment fail.
                • Prostate cancer may be detected by a physical exam or a high level of prostate-specific antigen (PSA) in the blood, but a biopsy is required for a definitive diagnosis. Prostate cancer is typically diagnosed relatively late in life, and is usually slow growing, so no treatment may be necessary. In younger patients or those with faster-growing tumors, treatment is likely to include surgery to remove the prostate, followed by chemotherapy and/or radiation therapy.
                    • Testicular cancer can be diagnosed by a physical exam and diagnostic tests, such as ultrasound or blood tests. Testicular cancer has one of the highest cure rates of all cancers. It is typically treated with surgery to remove the affected testis, and this may be followed by radiation therapy, and/or chemotherapy. Normal male reproductive functions are still possible after one testis is removed, if the remaining testis is healthy.
                      • The vagina is an elastic, muscular canal that can accommodate the penis. It is where sperm are usually ejaculated during sexual intercourse. The vagina is also the birth canal, and it channels the flow of menstrual blood from the uterus. A healthy vagina has a balance of symbiotic bacteria and an acidic pH .
                      • The uterus is a muscular organ above the vagina where a fetus develops. Its muscular walls contract to push out the fetus during childbirth. The cervix is the neck of the uterus that extends down into the vagina. It contains a canal connecting the vagina and uterus for sperm or an infant to pass through. The innermost layer of the uterus, the endometrium , thickens each month in preparation for an embryo but is shed in the following menstrual period if fertilization does not occur.
                      • The oviducts extend from the uterus to the ovaries. Waving fimbriae at the ovary ends of the oviducts guide ovulated ova into the tubes where fertilization may occur as the ova travel to the uterus. Cilia and peristalsis help eggs move through the tubes. Tubular fluid helps nourish sperm as they swim up the tubes toward eggs.
                      • The ovaries are gonads that produce eggs and secrete sex hormones including estrogen. Nests of cells called follicles in the ovarian cortex are the functional units of ovaries. Each follicle surrounds an immature ovum. At birth, a baby girl’s ovaries contain at least a million eggs, and they will not produce any more during her lifetime. One egg matures and is typically ovulated each month during a woman’s reproductive years.
                      • The vulva is a general term for external female reproductive organs. The vulva includes the clitoris , two pairs of labia , and openings for the urethra and vagina. Secretions from Bartholin’s glands near the vaginal opening lubricate the vulva.
                      • The breasts are technically not reproductive organs, but their mammary glands produce milk to feed an infant after birth. Milk drains through ducts and sacs and out through the nipple when a baby sucks.
                        • The average duration of pregnancy is 40 weeks (from the first day of the last menstrual period) and is divided into three trimesters of about three months each. Each trimester is associated with certain events and conditions that a pregnant woman may expect, such as morning sickness during the first trimester, feeling fetal movements for the first time during the second trimester, and rapid weight gain in both fetus and mother during the third trimester.
                        • Labour , which is the general term for the birth process, usually begins around the time the amniotic sac breaks and its fluid leaks out. Labour occurs in three stages: dilation of the cervix, birth of the baby, and delivery of the placenta (afterbirth).
                          • The female reproductive period is delineated by menarche , or the first menstrual period, which usually occurs around age 12 or 13 and by menopause , or the cessation of menstrual periods, which typically occurs around age 52. A typical menstrual cycle averages 28 days in length but may vary normally from 21 to 45 days. The average menstrual period is five days long, but may vary normally from two to seven days. These variations in the menstrual cycle may occur both between women and within individual women from month to month.
                          • The events of the menstrual cycle that take place in the ovaries make up the ovarian cycle . It includes the follicular phase , when a follicle and its ovum mature due to rising levels of FSH ovulation, when the ovum is released from the ovary due to a rise in estrogen and a surge in LH and the luteal phase , when the follicle is transformed into a structure called a corpus luteum that secretes progesterone. In a 28-day menstrual cycle, the follicular and luteal phases typically average about two weeks in length, with ovulation generally occurring around day 14 of the cycle.
                          • The events of the menstrual cycle that take place in the uterus make up the uterine cycle . It includes menstruation , which generally occurs on days 1 to 5 of the cycle and involves shedding of endometrial tissue that built up during the preceding cycle the proliferative phase , during which the endometrium builds up again until ovulation occurs and the secretory phase , which follows ovulation and during which the endometrium secretes substances and undergoes other changes that prepare it to receive an embryo .
                            • Cervical cancer occurs when cells of the cervix grow abnormally and develop the ability to invade nearby tissues, or spread to other parts of the body. Worldwide, cervical cancer is the second-most common type of cancer in females and the fourth-most common cause of cancer death in females. Early on, cervical cancer often has no symptoms later, symptoms such as abnormal vaginal bleeding and pain are likely.
                                • Most cases of cervical cancer occur because of infection with human papillomavirus (HPV) , so the HPV vaccine is expected to greatly reduce the incidence of the disease. Other risk factors include smoking and a weakened immune system. A Pap smear can diagnose cervical cancer at an early stage. Where Pap smears are done routinely, cervical cancer death rates have fallen dramatically. Treatment of cervical cancer generally includes surgery, which may be followed by radiation therapy or chemotherapy.
                                    • Diagnosis of vaginitis may be based on characteristics of the discharge, which can be examined microscopically or cultured. Treatment of vaginitis depends on the cause, and is usually an oral or topical anti-fungal or antibiotic medication.
                                        • Endometriosis is thought to have multiple causes, including genetic mutations. Retrograde menstruation may be the immediate cause of endometrial tissue escaping the uterus and entering the pelvic cavity. Endometriosis is usually treated with surgery to remove the abnormal tissue and medication for pain. If surgery is more conservative than hysterectomy, endometriosis may recur.
                                          • Treatments for infertility depend on the cause. For example, if a medical problem is interfering with sperm production, medication may resolve the underlying problem so sperm production is restored. Blockages in either the male or the female reproductive tract can often be treated surgically. If there are problems with ovulation, hormonal treatments may stimulate ovulation.
                                          • Some cases of infertility are treated with assisted reproductive technology (ART) . This is a collection of medical procedures in which eggs and sperm are taken from the couple and manipulated in a lab to increase the chances of fertilization occurring and an embryo forming. Other approaches for certain causes of infertility include the use of a surrogate mother, gestational carrier, or sperm donation.
                                            • Barrier methods are devices that block sperm from entering the uterus. They include condoms and diaphragms. Of all birth control methods, only condoms can also prevent the spread of sexually transmitted infections.
                                            • Hormonal methods involve the administration of hormones to prevent ovulation. Hormones can be administered in various ways, such as in an injection, through a skin patch, or, most commonly, in birth control pills. There are two types of birth control pills: those that contain estrogen and progesterone, and those that contain only progesterone. Both types are equally effective, but they have different potential side effects.
                                            • An intrauterine device (IUD) is a small T-shaped plastic structure containing copper or a hormone that is inserted into the uterus by a physician and left in place for months or even years. It is highly effective even with typical use, but it does have some risks, such as increased menstrual bleeding and, rarely, perforation of the uterus.
                                            • Behavioural methods involve regulating the timing or method of intercourse to prevent introduction of sperm into the female reproductive tract, either altogether or when an egg may be present. In fertility awareness methods, unprotected intercourse is avoided during the most fertile days of the cycle as estimated by basal body temperature or the characteristics of cervical mucus. In withdrawal, the penis is withdrawn from the vagina before ejaculation occurs. Behavioural methods are the least effective methods of contraception.
                                            • Sterilization is the most effective contraceptive method, but it requires a surgical procedure and may be irreversible. Male sterility is usually achieved with a vasectomy, in which the vas deferens are clamped or cut to prevent sperm from being ejaculated in semen. Female sterility is usually achieved with a tubal ligation, in which the oviducts are clamped or cut to prevent sperm from reaching and fertilizing eggs.
                                            • Emergency contraception is any form of contraception that is used after unprotected vaginal intercourse. One method is the “morning after” pill, which is a high-dose birth control pill that can be taken up to five days after unprotected sex. Another method is an IUD, which can be inserted up to five days after unprotected sex.

                                            In this chapter, you learned how the male and female reproductive systems work together to produce a zygote. In the next chapter, you will learn about how the human organism grows and develops throughout life — from a zygote all the way through old age.


                                            Table of contents

                                            Case 1 Steam Turbine Performance Degradation 1

                                            1.1.1 Steam Turbine Components 5

                                            1.1.2 Startup and Operation 7

                                            1.1.3 Performance Monitoring and Analysis 10

                                            1.1.4 Analyzing Performance Data &ndash Corrected Pressures 10

                                            1.1.5 Analyzing Performance Data &ndash Flow Function 12

                                            1.2.1 Steam Turbine Efficiency 14

                                            1.3.2 IP Turbine Enthalpy Drop 16

                                            1.4 Case Study Findings 17

                                            1.5 Decision Making and Actions 18

                                            1.5.2 Decision Making and Actions &ndash Alternatives 19

                                            1.5.3 Decision Making and Actions &ndash Making a Plan 20

                                            1.7 Symbols and Abbreviations 21

                                            Case 2 Risk / Reward Evaluation 26

                                            2.2.1 Types of Gas Turbine Generating Plants 29

                                            2.3 Gas Turbine Operating Risks 33

                                            2.3.1 Gas Turbine Major Maintenance 35

                                            2.3.2 Equivalent Fired Hours 36

                                            2.3.4 Reading Assignment 37

                                            2.4 Case Study Evaluations 38

                                            2.4.2 Presenting Results 39

                                            2.4.6 Exercise &ndash Sensitivities 41

                                            2.4.7 Presentation of Results 41

                                            Case 3 Gas Turbine Compressor Fouling 46

                                            3.1.2 Gas Compressor Fouling and Cleaning 49

                                            3.1.5 Gas Turbine Performance Measurement 52

                                            3.2.1 Derivative of the Cost Function 54

                                            3.2.3 Linear Programming 56

                                            3.2.4 New Methods &ndash New Thinking 56

                                            3.2.5 Exercise 3: Gas Turbine Inlet Filtration Upgrade 57

                                            3.2.6 Presenting Results 57

                                            3.3 Case Study Results / Closure 58

                                            3.4 Symbols and Abbreviations 60

                                            Case 4 Flow Instrument Degradation, Use and Placement 64

                                            4.1.1 Nuclear Steam Power Cycles 65

                                            4.1.2 Core Power-Level Measurement 67

                                            4.1.3 Differential Pressure Flow Measurement Devices 67

                                            4.1.4 Two-Phase Piping Pressure Drop 71

                                            4.5 Symbols and Abbreviations 76

                                            Case 5 Two-Phase Hydraulics 80

                                            5.1.1 Reading Assignment 83

                                            5.1.2 Müller-Steinhagen and Heck 83

                                            5.1.4 Pumping Net Positive Suction Head Required 86

                                            5.3.1 Liquid Flow to Reboiler 90

                                            5.3.2 Two-Phase Flow from Reboiler 90

                                            5.5 Symbols and Abbreviations 92

                                            Case 6 Reliability and Availability 95

                                            6.1.2 Availability: Planned and Unplanned Outages &ndash Parallel Systems 100


                                            Results

                                            Aggressive and nonaggressive prostate cancer cases and controls were similar with respect to age (Table I) median age at diagnosis for cases was 68 years (range 57–81 years). Sixty-eight percent of the combined cases were diagnosed 3 or more years after study entry (mean, 3.5 years). Cases had higher levels of PSA than controls (median, 3.5 vs. 1.2 ng/ml p < 0.001). Case diagnoses often followed an elevated PSA (57%), an abnormal DRE (14%) or both (17%) only 11% were diagnosed due to other reasons. Hormone levels tended to be strongly correlated among controls (p < 0.001 results not shown). Most serum hormone levels were not correlated with PSA in cases or controls, however, T:SHBG was correlated with PSA in controls (p < 0.05). With the exception of SHBG, serum hormone levels were inversely associated with age.

                                            Demographics, N (%) Prostate cancer cases Controls (N = 889)
                                            Aggressive cases (N = 277) Nonaggressive cases (N = 450)
                                            Age (years)
                                            55–59 34 (12.3) 57 (12.7) 118 (13.3)
                                            60–64 88 (31.8) 152 (33.8) 293 (33.0)
                                            65–69 106 (38.3) 151 (33.6) 313 (35.2)
                                            70–74 49 (17.7) 90 (20.0) 165 (18.6)
                                            BMI (kg/m 2 )
                                            <25.0 82 (29.6) 116 (25.8) 243 (27.3)
                                            25.0–29.9 150 (54.2) 249 (55.3) 461 (51.9)
                                            ≥30 45 (16.2) 85 (18.9) 185 (20.8)
                                            Diabetes
                                            No 266 (96.0) 420 (93.3) 820 (92.2)
                                            Yes 11 (4.2) 30 (6.7) 69 (7.8)
                                            Ever smoker
                                            No 126 (45.7) 198 (44.0) 355 (39.9)
                                            Yes 150 (54.3) 252 (56.0) 534 (60.1)
                                            Study year
                                            1–2 163 (58.8) 271 (60.2) 542 (61.0)
                                            3–4 73 (26.4) 141 (31.3) 254 (28.6)
                                            ≥5 41 (14.8) 38 (8.4) 93 (10.5)
                                            PSA (ng/ml), median (IQR) 3.4 (2.4–4.9) 3.6 (2.4–5.0) 1.2 (0.7–2.1)

                                            Risks tended to increase with greater total, free and bioavailable T, and to decrease with greater SHBG, but these findings were not statistically significant (Table II). T:SHBG ratio, however, was associated with increased risk for prostate cancer [highest quartile OR 1.54, 95% confidence interval (CI) 1.13–2.10 ptrend = 0.01]. Δ4-A and 3α-dG were not associated with overall prostate cancer risk.

                                            Quartiles p-trend
                                            1 2 3 4
                                            Δ4-A (ng/ml)
                                            Cases/controls 187/222 166/223 190/222 184/222
                                            Median, IQR 0.77, 0.66–0.87 1.07, 1.00–1.12 1.34, 1.26–1.41 1.77, 1.62–2.02
                                            OR (95% CI)1 1 Conditional OR, matched on age at randomization, fiscal year of first screen, and study year of diagnosis/reference mutual adjustment for Δ4-A, T, SHBG and 3α-diolG.
                                            Reference 0.86 (0.64, 1.14) 1.00 (0.75, 1.35) 0.96 (0.70, 1.32) 0.76
                                            T (ng/ml)
                                            Cases/controls 163/222 202/223 182/222 180/220
                                            Median, IQR 2.68, 2.29–3.07 4.02, 3.72–4.35 5.31, 4.99–5.76 7.78, 6.91–9.34
                                            OR (95% CI)1 1 Conditional OR, matched on age at randomization, fiscal year of first screen, and study year of diagnosis/reference mutual adjustment for Δ4-A, T, SHBG and 3α-diolG.
                                            Reference 1.32 (0.97, 1.73) 1.29 (0.97, 1.73) 1.39 (0.92, 2.08) 0.22
                                            SHBG (nmol/l)
                                            Cases/controls 192/222 177/223 188/222 169/222
                                            Median, IQR 25.62, 20.85–30.08 37.78, 35.07–40.98 50.60, 47.23–54.16 73.67, 64.86–91.09
                                            OR (95% CI)1 1 Conditional OR, matched on age at randomization, fiscal year of first screen, and study year of diagnosis/reference mutual adjustment for Δ4-A, T, SHBG and 3α-diolG.
                                            Reference 0.84 (0.63, 1.14) 0.86 (0.62, 1.20) 0.76 (0.52, 1.10) 0.22
                                            T:SHBG
                                            Cases/controls 152/221 182/222 177/222 215/222
                                            Median, IQR 0.07, 0.06–0.08 0.09, 0.09–0.10 0.12, 0.11–0.12 0.16, 0.14–0.18
                                            OR (95% CI)2 2 Conditional OR, matched on age at randomization, fiscal year of first screen, and study year of diagnosis/reference adjustment for Δ4-A and 3α-diolG.
                                            Reference 1.24 (0.92, 1.66) 1.21 (0.90, 1.63) 1.54 (1.13, 2.10) 0.01
                                            Free T (nmol/l)
                                            Cases/controls 168/222 189/221 181/222 188/222
                                            Median, IQR 0.23, 0.20–0.25 0.30, 0.29–0.32 0.37, 0.35–0.39 0.47, 0.44–0.54
                                            OR (95% CI)2 2 Conditional OR, matched on age at randomization, fiscal year of first screen, and study year of diagnosis/reference adjustment for Δ4-A and 3α-diolG.
                                            Reference 1.15 (0.86, 1.52) 1.08 (0.80, 1.45) 1.20 (0.87, 1.65) 0.36
                                            Bioavailable T (nmol/l)
                                            Cases/controls 160/222 194/222 192/221 180/222
                                            Median, IQR 3.24, 2.84–3.61 4.53, 4.26–4.87 5.79, 5.48–6.15 7.91, 7.15–9.12
                                            OR (95% CI)2 2 Conditional OR, matched on age at randomization, fiscal year of first screen, and study year of diagnosis/reference adjustment for Δ4-A and 3α-diolG.
                                            Reference 1.23 (0.92, 1.64) 1.24 (0.92, 1.67) 1.20 (0.87, 1.66) 0.37
                                            3α-diolG (ng/ml)
                                            Cases/controls 168/222 185/222 222/223 152/222
                                            Median, IQR 3.22, 2.45–3.65 5.38, 4.76–6.09 8.31, 7.58–9.39 14.10, 12.19–17.35
                                            OR (95% CI)1 1 Conditional OR, matched on age at randomization, fiscal year of first screen, and study year of diagnosis/reference mutual adjustment for Δ4-A, T, SHBG and 3α-diolG.
                                            Reference 1.10 (0.83, 1.46) 1.29 (0.97, 1.73) 0.87 (0.60, 1.18) 0.31
                                            • 1 Conditional OR, matched on age at randomization, fiscal year of first screen, and study year of diagnosis/reference mutual adjustment for Δ4-A, T, SHBG and 3α-diolG.
                                            • 2 Conditional OR, matched on age at randomization, fiscal year of first screen, and study year of diagnosis/reference adjustment for Δ4-A and 3α-diolG.

                                            Risks were elevated in older men in relation to serum T greater than the lowest quartile, but risks did not increase in a dose–response fashion over the total range of this analyte. (Table III). Similar patterns were also noted for free T and bioavailable T. The overall association of greater T:SHBG with increased prostate cancer risk was due to risks in men 65 years of age or older (Table III ptrend = 0.001), with risks rising to greater than 2-fold in the highest T:SHBG quartile (OR 2.07, 95% CI: 1.33–3.21). Increased risks for Δ4-A and 3α-diolG were suggested only in younger men (pint = 0.04 and pint = 0.004, respectively).

                                            Quartiles p-trend p-int
                                            1 2 3 4
                                            Age < 65 years (n = 742)
                                            Δ4-A (ng/ml) 60/88 73/78 84/114 114/131
                                            OR (95% CI)2 2 Conditional OR, matched on age at randomization, fiscal year of first screen, and study year of diagnosis/reference mutual adjustment for Δ4-A, T, SHBG, and 3α-diolG.
                                            Reference 1.38 (0.85, 2.25) 1.06 (0.66, 1.72) 1.24 (0.76, 2.03) 0.39
                                            T (ng/ml) 78/99 75/96 82/103 96/113
                                            OR (95% CI)2 2 Conditional OR, matched on age at randomization, fiscal year of first screen, and study year of diagnosis/reference mutual adjustment for Δ4-A, T, SHBG, and 3α-diolG.
                                            Reference 0.94 (0.59, 1.49) 0.95 (0.57, 1.59) 1.00 (0.54, 1.82) 0.85
                                            SHBG (nmol/l) 91/109 75/102 84/102 81/98
                                            OR (95% CI)2 2 Conditional OR, matched on age at randomization, fiscal year of first screen, and study year of diagnosis/reference mutual adjustment for Δ4-A, T, SHBG, and 3α-diolG.
                                            Reference 0.91 (0.58, 1.41) 0.98 (0.60, 1.60) 0.99 (0.57, 1.73) 0.96
                                            T:SHBG 62/94 88/92 73/93 108/132
                                            OR (95% CI)3 3 Conditional OR, matched on age at randomization, fiscal year of first screen, and study year of diagnosis/reference adjustment for Δ4-A and 3α-diolG.
                                            Reference 1.35 (0.86, 2.11) 1.11 (0.70, 1.77) 1.17 (0.73, 1.84) 0.71
                                            Free T (nmol/l) 76/95 73/102 84/100 98/114
                                            OR (95% CI)3 3 Conditional OR, matched on age at randomization, fiscal year of first screen, and study year of diagnosis/reference adjustment for Δ4-A and 3α-diolG.
                                            Reference 0.85 (0.55, 1.32) 0.95 (0.60, 1.48) 1.02 (0.63, 1.64) 0.64
                                            Bioavailable T (nmol/l) 73/93 76/103 85/102 97/113
                                            OR (95% CI)3 3 Conditional OR, matched on age at randomization, fiscal year of first screen, and study year of diagnosis/reference adjustment for Δ4-A and 3α-diolG.
                                            Reference 0.90 (0.58, 1.41) 0.98 (0.63, 1.55) 1.04 (0.64, 1.68) 0.65
                                            3α-diolG (ng/ml) 52/99 89/93 117/103 73/116
                                            OR (95% CI)2 2 Conditional OR, matched on age at randomization, fiscal year of first screen, and study year of diagnosis/reference mutual adjustment for Δ4-A, T, SHBG, and 3α-diolG.
                                            Reference 1.89 (1.20, 2.99) 2.25 (1.43, 3.55) 1.22 (0.76, 1.98) 0.73
                                            Age ≥ 65 years (n = 874)
                                            Δ4-A (ng/ml) 127/134 93/145 106/108 70/91
                                            OR (95% CI)2 2 Conditional OR, matched on age at randomization, fiscal year of first screen, and study year of diagnosis/reference mutual adjustment for Δ4-A, T, SHBG, and 3α-diolG.
                                            Reference 0.67 (0.46, 0.96) 1.04 (0.71, 1.52) 0.78 (0.50, 1.22) 0.10 0.04
                                            T (ng/ml) 85/123 127/127 100/119 84/107
                                            OR (95% CI)2 2 Conditional OR, matched on age at randomization, fiscal year of first screen, and study year of diagnosis/reference mutual adjustment for Δ4-A, T, SHBG, and 3α-diolG.
                                            Reference 1.74 (1.15, 2.63) 1.63 (1.03, 2.59) 1.86 (1.05, 3.29) 0.14 0.61
                                            SHBG (nmol/l) 101/113 102/121 104/120 88/124
                                            OR (95% CI)2 2 Conditional OR, matched on age at randomization, fiscal year of first screen, and study year of diagnosis/reference mutual adjustment for Δ4-A, T, SHBG, and 3α-diolG.
                                            Reference 0.75 (0.49, 1.13) 0.77 (0.49, 1.21) 0.57 (0.34, 0.98) 0.10 0.79
                                            T:SHBG 90/127 94/130 104/129 107/90
                                            OR (95% CI)3 3 Conditional OR, matched on age at randomization, fiscal year of first screen, and study year of diagnosis/reference adjustment for Δ4-A and 3α-diolG.
                                            Reference 1.11 (0.75, 1.65) 1.27 (0.86, 1.89) 2.07 (1.33, 3.21) <0.01 0.12
                                            Free T (nmol/l) 92/127 116/119 97/122 90/108
                                            OR (95% CI)3 3 Conditional OR, matched on age at randomization, fiscal year of first screen, and study year of diagnosis/reference adjustment for Δ4-A and 3α-diolG.
                                            Reference 1.46 (1.00, 2.14) 1.24 (0.82, 1.86) 1.37 (0.88, 2.14) 0.21 0.49
                                            Bioavailable T (nmol/l) 87/129 118/119 107/119 83/109
                                            OR (95% CI)3 3 Conditional OR, matched on age at randomization, fiscal year of first screen, and study year of diagnosis/reference adjustment for Δ4-A and 3α-diolG.
                                            Reference 1.57 (1.07, 2.31) 1.52 (1.01, 2.29) 1.33 (0.85, 2.09) 0.42 0.44
                                            3α-diolG (ng/ml) 116/123 96/129 105/120 79/106
                                            OR (95% CI)2 2 Conditional OR, matched on age at randomization, fiscal year of first screen, and study year of diagnosis/reference mutual adjustment for Δ4-A, T, SHBG, and 3α-diolG.
                                            Reference 0.76 (0.52, 1.10) 0.86 (0.58, 1.26) 0.71 (0.47, 1.09) 0.26 <0.01
                                            • 1 Case/control number provided for each stratum.
                                            • 2 Conditional OR, matched on age at randomization, fiscal year of first screen, and study year of diagnosis/reference mutual adjustment for Δ4-A, T, SHBG, and 3α-diolG.
                                            • 3 Conditional OR, matched on age at randomization, fiscal year of first screen, and study year of diagnosis/reference adjustment for Δ4-A and 3α-diolG.

                                            More pronounced risks associated with elevated total T (Q4 vs. Q1: OR 1.84, 95% CI 1.06–3.17 ptrend = 0.12) and T:SHBG (Q4 vs. Q1: OR 1.73, 95% CI 1.12–2.66 ptrend = 0.06) were observed for aggressive than nonaggressive disease, although tests of heterogeneity between groups were not significant (results not shown). Similar risks of aggressive disease were observed for free T and bioavailable T, while no notable differences by disease aggressiveness were observed for Δ4-A and 3α-dG.

                                            When age differentials in risk were further examined by disease aggressiveness, the excess risks noted in older men were found to be largely due to risks for aggressive disease (Table IV), with excess risks noted at the higher levels of T (ptrend = 0.05) and T:SHBG (ptrend = 0.005) trends were not significant for free T (ptrend = 0.14) and bioavailable T (ptrend = 0.23). Decreased risks were noted at the higher levels of SHBG (Q4 vs. Q1: OR 0.45, 95% CI 0.23–0.89), however, trends were not significant (ptrend = 0.06). A trend of decreasing risks was noted at the higher levels of 3α-diolG (p = 0.05) in older men. Although nonaggressive prostate cancer showed weaker associations with most hormone-related analytes in older men, risk of nonaggressive disease was significantly elevated at the higher range of T:SHBG (ptrend = 0.02).

                                            Quartiles p-trend
                                            1 2 3 4
                                            Age <65 years (N = 742)
                                            Nonaggressive disease (N = 209 cases)
                                            Δ4-A (ng/ml)2 2 Polytomous logistic regression, adjusted for matching variables (age at randomization, fiscal year of first screen, study year of diagnosis/reference) mutual adjustment for Δ4-A, T, SHBG and 3α-diolG.–
                                            Reference 1.04 (0.59, 1.82) 0.97 (0.58, 1.64) 1.01 (0.60, 1.72) 0.71
                                            T (ng/ml)1 1 Aggressive disease defined as Gleason ≥ 7 or Stage III/IV.–
                                            , 2 2 Polytomous logistic regression, adjusted for matching variables (age at randomization, fiscal year of first screen, study year of diagnosis/reference) mutual adjustment for Δ4-A, T, SHBG and 3α-diolG.–
                                            Reference 0.91 (0.54, 1.55) 0.89 (0.50, 1.59) 1.06 (0.55, 2.06) 0.72
                                            SHBG (nmol/l)1 1 Aggressive disease defined as Gleason ≥ 7 or Stage III/IV.–
                                            , 2 2 Polytomous logistic regression, adjusted for matching variables (age at randomization, fiscal year of first screen, study year of diagnosis/reference) mutual adjustment for Δ4-A, T, SHBG and 3α-diolG.–
                                            Reference 0.98 (0.60, 1.61) 0.88 (0.50, 1.54) 0.90 (0.48, 1.69) 0.70
                                            T:SHBG3 3 Polytomous logistic regression, adjusted for matching variables, Δ4-A and 3α-diolG.
                                            Reference 1.19 (0.71, 2.00) 0.99 (0.58, 1.68) 1.18 (0.72, 1.95) 0.54
                                            Free T (nmol/l)3 3 Polytomous logistic regression, adjusted for matching variables, Δ4-A and 3α-diolG.
                                            Reference 0.70 (0.42, 1.17) 0.78 (0.47, 1.30) 1.00 (0.60, 1.69) 0.57
                                            Bioavailable T (nmol/l)1 1 Aggressive disease defined as Gleason ≥ 7 or Stage III/IV.–
                                            , 3 3 Polytomous logistic regression, adjusted for matching variables, Δ4-A and 3α-diolG.
                                            Reference 0.78 (0.47, 1.29) 0.85 (0.51, 1.41) 0.93 (0.55, 1.57) 0.87
                                            3α-diolG (ng/ml)2 2 Polytomous logistic regression, adjusted for matching variables (age at randomization, fiscal year of first screen, study year of diagnosis/reference) mutual adjustment for Δ4-A, T, SHBG and 3α-diolG.–
                                            Reference 2.35 (1.36, 4.05) 2.79 (1.63, 4.79) 1.36 (0.76, 2.43) 0.79
                                            Aggressive disease (N = 122 cases)
                                            Δ4-A (ng/ml)2 2 Polytomous logistic regression, adjusted for matching variables (age at randomization, fiscal year of first screen, study year of diagnosis/reference) mutual adjustment for Δ4-A, T, SHBG and 3α-diolG.–
                                            Reference 2.05 (1.05, 4.02) 1.16 (0.58, 2.29) 1.61 (0.83, 3.14) 0.36
                                            T (ng/ml)1 1 Aggressive disease defined as Gleason ≥ 7 or Stage III/IV.–
                                            , 2 2 Polytomous logistic regression, adjusted for matching variables (age at randomization, fiscal year of first screen, study year of diagnosis/reference) mutual adjustment for Δ4-A, T, SHBG and 3α-diolG.–
                                            Reference 0.99 (0.51, 1.92) 1.06 (0.52, 2.15) 0.94 (0.42, 2.12) 0.95
                                            SHBG (nmol/l)1 1 Aggressive disease defined as Gleason ≥ 7 or Stage III/IV.–
                                            , 2 2 Polytomous logistic regression, adjusted for matching variables (age at randomization, fiscal year of first screen, study year of diagnosis/reference) mutual adjustment for Δ4-A, T, SHBG and 3α-diolG.–
                                            Reference 0.65 (0.34, 1.23) 1.05 (0.54, 2.02) 0.97 (0.46, 2.06) 0.91
                                            T:SHBG3 3 Polytomous logistic regression, adjusted for matching variables, Δ4-A and 3α-diolG.
                                            Reference 1.61 (0.86, 3.04) 1.31 (0.68, 2.52) 1.10 (0.58, 2.09) 0.94
                                            Free T (nmol/l)3 3 Polytomous logistic regression, adjusted for matching variables, Δ4-A and 3α-diolG.
                                            Reference 1.13 (0.61, 2.12) 1.27 (0.68, 2.35) 0.97 (0.50, 1.88) 0.95
                                            Bioavailable T (nmol/l)1 1 Aggressive disease defined as Gleason ≥ 7 or Stage III/IV.–
                                            , 3 3 Polytomous logistic regression, adjusted for matching variables, Δ4-A and 3α-diolG.
                                            Reference 1.10 (0.58, 2.07) 1.20 (0.64, 2.27) 1.16 (0.60, 2.24) 0.55
                                            3α-diolG (ng/ml)2 2 Polytomous logistic regression, adjusted for matching variables (age at randomization, fiscal year of first screen, study year of diagnosis/reference) mutual adjustment for Δ4-A, T, SHBG and 3α-diolG.–
                                            Reference 1.34 (0.72, 2.52) 1.57 (0.85, 2.90) 1.04 (0.54, 2.00) 0.79
                                            Age ≥ 65 years (N = 874)
                                            Nonaggressive disease (N = 241 cases)
                                            Δ4-A (ng/ml)2 2 Polytomous logistic regression, adjusted for matching variables (age at randomization, fiscal year of first screen, study year of diagnosis/reference) mutual adjustment for Δ4-A, T, SHBG and 3α-diolG.–
                                            Reference 0.75 (0.49, 1.14) 1.02 (0.66, 1.57) 0.70 (0.42, 1.19) 0.36
                                            T (ng/ml)1 1 Aggressive disease defined as Gleason ≥ 7 or Stage III/IV.–
                                            , 2 2 Polytomous logistic regression, adjusted for matching variables (age at randomization, fiscal year of first screen, study year of diagnosis/reference) mutual adjustment for Δ4-A, T, SHBG and 3α-diolG.–
                                            Reference 1.34 (0.83, 2.17) 1.46 (0.86, 2.47) 1.33 (0.70, 2.53) 0.64
                                            SHBG (nmol/l)1 1 Aggressive disease defined as Gleason ≥ 7 or Stage III/IV.–
                                            , 2 2 Polytomous logistic regression, adjusted for matching variables (age at randomization, fiscal year of first screen, study year of diagnosis/reference) mutual adjustment for Δ4-A, T, SHBG and 3α-diolG.–
                                            Reference 0.83 (0.51, 1.33) 1.01 (0.61, 1.67) 0.66 (0.37, 1.19) 0.37
                                            T:SHBG3 3 Polytomous logistic regression, adjusted for matching variables, Δ4-A and 3α-diolG.
                                            Reference 0.82 (0.52, 1.29) 0.99 (0.63, 1.55) 1.72 (1.08, 2.76) 0.02
                                            Free T (nmol/l)3 3 Polytomous logistic regression, adjusted for matching variables, Δ4-A and 3α-diolG.
                                            Reference 1.25 (0.80, 1.95) 1.14 (0.72, 1.81) 1.08 (0.65, 1.80) 0.96
                                            Bioavailable T (nmol/l)1 1 Aggressive disease defined as Gleason ≥ 7 or Stage III/IV.–
                                            , 3 3 Polytomous logistic regression, adjusted for matching variables, Δ4-A and 3α-diolG.
                                            Reference 1.30 (0.83, 2.03) 1.35 (0.85, 2.15) 1.09 (0.65, 1.83) 0.89
                                            3α-diolG (ng/ml)2 2 Polytomous logistic regression, adjusted for matching variables (age at randomization, fiscal year of first screen, study year of diagnosis/reference) mutual adjustment for Δ4-A, T, SHBG and 3α-diolG.–
                                            Reference 0.70 (0.45, 1.10) 0.85 (0.54, 1.33) 0.89 (0.55, 1.44) 0.99
                                            Aggressive disease (N = 155 cases)
                                            Δ4-A (ng/ml)2 2 Polytomous logistic regression, adjusted for matching variables (age at randomization, fiscal year of first screen, study year of diagnosis/reference) mutual adjustment for Δ4-A, T, SHBG and 3α-diolG.–
                                            Reference 0.53 (0.31, 0.90) 1.02 (0.61, 1.69) 0.91 (0.51, 1.63) 0.60
                                            T (ng/ml)1 1 Aggressive disease defined as Gleason ≥ 7 or Stage III/IV.–
                                            , 2 2 Polytomous logistic regression, adjusted for matching variables (age at randomization, fiscal year of first screen, study year of diagnosis/reference) mutual adjustment for Δ4-A, T, SHBG and 3α-diolG.–
                                            Reference 2.74 (1.51, 4.92) 1.98 (1.00, 3.91) 3.29 (1.51, 7.18) 0.05
                                            SHBG (nmol/l)1 1 Aggressive disease defined as Gleason ≥ 7 or Stage III/IV.–
                                            , 2 2 Polytomous logistic regression, adjusted for matching variables (age at randomization, fiscal year of first screen, study year of diagnosis/reference) mutual adjustment for Δ4-A, T, SHBG and 3α-diolG.–
                                            Reference 0.64 (0.37, 1.11) 0.48 (0.26, 0.88) 0.45 (0.23, 0.89) 0.06
                                            T:SHBG3 3 Polytomous logistic regression, adjusted for matching variables, Δ4-A and 3α-diolG.
                                            Reference 1.84 (1.05, 3.23) 2.02 (1.14, 3.56) 2.76 (1.50, 5.09) <0.01
                                            Free T (nmol/l)3 3 Polytomous logistic regression, adjusted for matching variables, Δ4-A and 3α-diolG.
                                            Reference 1.87 (1.09, 3.21) 1.43 (0.80, 2.56) 1.97 (1.07, 3.61) 0.14
                                            Bioavailable T (nmol/l)1 1 Aggressive disease defined as Gleason ≥ 7 or Stage III/IV.–
                                            ,3
                                            Reference 2.18 (1.26, 3.77) 1.85 (1.03, 3.32) 1.84 (0.98, 3.45) 0.23
                                            3α-diolG (ng/ml)2 2 Polytomous logistic regression, adjusted for matching variables (age at randomization, fiscal year of first screen, study year of diagnosis/reference) mutual adjustment for Δ4-A, T, SHBG and 3α-diolG.–
                                            Reference 0.84 (0.50, 1.40) 0.85 (0.50, 1.43) 0.52 (0.28, 0.97) 0.05
                                            • 1 Aggressive disease defined as Gleason ≥ 7 or Stage III/IV.–
                                            • 2 Polytomous logistic regression, adjusted for matching variables (age at randomization, fiscal year of first screen, study year of diagnosis/reference) mutual adjustment for Δ4-A, T, SHBG and 3α-diolG.–
                                            • 3 Polytomous logistic regression, adjusted for matching variables, Δ4-A and 3α-diolG.

                                            Risks of prostate cancer for the measured hormones did not differ by BMI, family history or year on study (data not shown).


                                            4. DISCUSSION

                                            The risk of developing HNSCC is much higher for men than for women, a gap which is incompletely explained by gender discrepancies in exposure to alcohol and tobacco. This has led some to theorize that hormonal differences may, in part, account for this disparity in disease. However, there is a paucity of research reports surrounding female-specific risk factors of HNSCC. In this report, we enhance the sparse literature with an analysis of female reproductive factors and hormone use stemming from a case-control on female HNSCC.

                                            We report no significant associations of female reproductive factors with HNSCC. Very few studies have addressed the topic of reproductive history and HNSCC, with inconsistent results. To our knowledge, ours is the only study to evaluate the association of fertility medication use and HNSCC and to assess number of pregnancies, independent of parity. In agreement with our results, in a large cohort study of 297 female HNSCC patients, Freedman et al [10] observed no significant associations between HNSCC and age at menarche, hysterectomy/oophorectomy status, oral contraceptive use, parity or age at first live birth. Others have reported on the role of female reproductive factors and HNSCC with conflicting results. A case-control study involving 195 women with oral or pharyngeal cancer [22] showed no association with several reproductive factors, but identified a protective effect of late menopause and lower parity a small study from the same group on 68 women with laryngeal cancer [23] report an association with late menarche (≥ 15 years). In a large case-control study (530 cases and 530 controls), Suba et al [11] found associations between cancer of the oral cavity and early age at menopause and hysterectomy and/or oophorectomy. The results of these three studies are incongruent, and collectively there is no clear evidence in the literature for involvement of any single female reproductive characteristic with HNSCC.

                                            Our study presents marginal evidence that the use of hormone replacement therapy (HRT) may confer a protective effect against HNSCC, with a borderline inverse dose-response across categories of increasing duration. These findings are in-line with those of Freeman and colleagues [8] who report a relative risk of 0.78 (95% CI: 0.61-0.99), although several others found no association [11 23 24 25]. Part of the inconsistency may be attributed to heterogeneity among studies, which reflects the diversity of the populations and of the type of exposure all of the studies but one (Freedman) were conducted in various parts of Europe. Exogenous hormonal exposures, such as HRT and oral contraception, vary between Europe and US. For example, a study based on pharmaceutical sales data from the 1990s, prior to the decline in use of HRT, reports substantial differences in use of HRT between the United States and Europe [26]. HRT is available in many different forms, with varying doses depending upon the drug and the needs of the patient [9], although use drastically declined following the publication of the Women’s Health Initiative trial results in 2002 [27 28]. The composition of oral contraceptives are similarly variable [29]. Differences in study design are also present: out of 6 studies conducted on this topic, 2 are cohort and 4 are case-control studies, one includes larynx, one oral cavity, the other 4 head and neck tumors. thus making the comparison across studies very difficult.

                                            While the mechanisms behind the potential protective effect of HRT are largely unknown, a role in alteration of HNSCC risk is biologically plausible, as the head and neck epithelium undergoes gender-specific changes during puberty [30 31]. This is particularly evident in the larynx, although the present study is too small to properly evaluate the effect in a site-specific manner. Sex hormone receptors are present in both benign [12 13 14 15] and malignant [16 17 18] head and neck tissue. ERβ functions as a tumor suppressor via inhibition of proliferation and induction of differentiation and apoptosis [32 33], which could potentially eliminate precancerous defect cells prior to malignant conversion, and may be the prevalent subtype of estrogen receptor expressed in the head and neck: a study of benign buccal and gingival epithelium [12] reported ERβ to be widely expressed, while ERα, which appears to act as a tumor promoter through stimulation of cellular proliferation [34 35], was not detected.

                                            The major strengths of this study include the collection of detailed exposure history for female reproductive factors for assessment, as well as detailed collection of other potentially confounding exposures, such as smoking dose, educational attainment and family history of cancer. However, there were also several limitations to this study. There may have been insufficient statistical power for detection of certain associations, due to our moderate sample size, and therefore larger scale studies are needed before ruling out small to moderate effects. Additionally, although the statistical models were adjusted for smoking dose, there is a potential for residual confounding due to the categorization of the covariate. It should be noted, however, that the ORs for postmenopausal hormone use among never-smokers, although imprecise, were consistent with the adjusted ORs for postmenopausal hormone use among the greater study population. Another issue is that we did not have specific data regarding type of HRT drug used or the dosage, even though there are many different kinds available with differing doses and forms of hormones. Likewise, our study does not include data on the type of oral contraception used.

                                            The findings of this study do not support a link between HNSCC and reproductive factors, but the evidence is not sufficient to fully refute the hormonal theory. The borderline association of HRT with HNSCC may warrant further evaluation in future studies that should include larger study populations, with more in-depth examination of the effects of specific forms and doses of HRT and oral contraception. Future studies should also seek to evaluate the effects of estrogen and metabolite levels on HNSCC risk. Continued assessment of hormonal and non-hormonal gender differences may eventually provide insight as to why men have substantially higher incidence of this disease and advance our knowledge regarding the development of head and neck cancer.


                                            Mr. Sabol is an engineer with broad experience in the power industry, detailed design, and asset management. His accomplishments include writing of computer programs, detailed fluid system designs, engineering designs for the destruction of chemical weapons, resolution of complex engineering problems, engineering project management, and management of power generating assets. He graduated from Virginia Polytechnic Institute and State University in Mechanical Engineering, holds a Professional Engineer&rsquos license in the State of Texas and is a certified Project Management Professional. His published works relate to the use of modelling programs, maintenance optimization, and woodworking techniques. Currently residing in Texas, Mr. Sabol provides consulting services.

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