Sex Differences in the Transmission, Prevention, and Disease Manifestations of Sexually Transmitted Diseases FREE

Sexually transmitted diseases (STDs) cause significant disease burden in developed and underdeveloped countries.^1- 2 Dermatological manifestations of STDs, ranging from full body papulosquamous eruptions to genital ulcers and warts, prompt health care providers (namely, physicians, nurses, physician's assistants, and other clinic personnel involved directly in patient care) to search for viral or bacterial infections that have significant consequences to the overall health and well-being of the infected person. The cutaneous manifestations of STDs and the transmission of STDs have been altered by the spread of the human immunodeficiency virus (HIV). Common STDs can influence transmission of HIV.^2- 3

Sexually transmitted disease transmission, prevalence, and disease burden are not shared equally between the sexes. Because of economic, biological, and social factors,^4- 5 women are more susceptible than men for the acquisition of HIV and other STDs. Once they have contracted STDs, women often sustain more damage to their health than do men. This review article elucidates the differential effect of STDs on women vs men to better understand what is required to protect women from the morbidity and mortality of STDs. Also, a brief review of the sex differences in clinical manifestations and prevention of STDs is given in Table 1 and Table 2, respectively.

Biological, social, and behavioral factors are responsible for the increased rate of transmission of STDs in women. Sexually transmitted diseases can be transmitted by breaks in mucosal surfaces that are exposed to infected bodily fluids.⁶ During sexual behaviors, women have a greater surface area of mucous membranes exposed and more trauma to those exposed mucosal tissues than do men; therefore, women are at greater risk of contracting STDs from infected male partners.⁷ Mucosal involvement in STD transmission led to many new therapies, including vaccines, aimed at enhancing the barrier function of mucosal surfaces, either through physical barriers or by stimulating the immune system.

Biologically, STDs are defined by 4 major categories: genital ulcer diseases, human papillomavirus (HPV), genital discharge diseases, and HIV.

Chancroid, lymphogranuloma venereum, granuloma inguinale, syphilis, and human herpesvirus (HSV) are genital ulcer diseases that are transmitted through skin-to-skin contact from ulcers or infected skin that appears normal.

Chancroid, lymphogranuloma venereum, and granuloma inguinale, which are ulcerative diseases endemic in developing countries, place infected individuals at greater risk for other STDs, including HIV.⁸ While the incidence of all 3 diseases has decreased because of safe and effective medical therapies, significant disease morbidity can occur.

Chancroid, which is most commonly seen in Africa, the Caribbean, and southeast Asia, is characterized by genital ulcers with regional invasion without any systemic manifestations. The main reservoir for disease transmission is prostitutes. It is caused by the anaerobic bacterium Haemophilus ducreyi, which penetrates defects in the epidermis to cause inflammation via the influx of lymphocytes, macrophages, and granulocytes.⁸ Men are more likely to develop painful inguinal lymphadenitis and multiple ulcers.

Lymphogranuloma venereum, caused by Chlamydia trachomatis, enters via microscopic defects in mucous membranes. It is endemic to areas of Africa, Asia, India, and South America, and affects men more often than it does women. Clinical manifestations can be separated into primary lesions, most commonly a herpetiform lesion; secondary lesions characterized by an inguinal syndrome; and months to years later, the anogenitorectal syndrome characterized by proctocolitis. The latter stage is more common in women and homosexual men who engage in receptive anal sex.⁹

Granuloma inguinale, or donovanosis, is an ulcerative STD caused by Calymmatobacterium granulomatis, and it remains endemic in South Africa, India, and other developing areas. Lesions, besides being ulcerative, are indolent, progressive, and granulomatous. No sexual predominance is noted.¹⁰ Antibiotics are the mainstay of treatment and are effective in all 3 diseases.

Primary syphilis, which is caused by the spirochete Treponema pallidum, is characterized by a painless chancre. Secondary syphilis is characterized by hematogenous spread of disease. The overwhelming women's health concern is infection during pregnancy.⁸ About one third of untreated patients develop tertiary syphilis, whose latency period lasts years to decades and which manifests as gummatous or cardiovascular syphilis or neurosyphilis.

Women are more likely than men to have HSV 2 infection, which is probably owing to more of the female genitalia lacking an intact stratum corneum¹¹; thus, many preventive measures are more efficacious in women. Human herpesvirus vaccination was greater than 70% efficacious in preventing HSV in women who did not have HSV 1 or HSV 2.¹² The same protective effect was not shown in men who were HSV 1 and HSV 2 negative and received the vaccine. In addition, antibodies to HSV 1 were protective against acquiring HSV 2 in women. However, men who had HSV 1 infection had a less protective effect against acquiring HSV 2.¹² The vaccine was safe and judged more immunogenic in women. When compared with natural infections, the vaccine produced higher levels of antibody 13 months after immunization.¹³ Researchers^12- 13 theorized that the enhanced T helper cell 1 responses observed in women with various other diseases might account for the sex-specific differences observed in this study.

Preventative measures, such as male condoms, also provided a greater preventative benefit for female partners. A study evaluating 528 discordant couples found that condom use during more than 25% of sex acts was associated with protection against HSV 2 acquisition for women but not for men. The risk of HSV 2 transmission declined from 8.5 per 100 person-years to 0.9 per 100 person-years with the use of condoms and changes in sexual activity, specifically, counseling to avoid sex acts when the infected partner had visible lesions.¹⁴ Condoms provide a lesser degree of protection for genital ulcer diseases when compared with discharge diseases such as gonorrhea, chlamydia, and trichomoniasis. One explanation for this observation is that genital ulcer infections are transmitted by exposure to areas (eg, infected skin or mucosal surfaces) that are not covered or protected by the condom.¹⁵ However, condoms can still provide significant protection when used consistently and properly. The female condom may provide more protection than the male condom in these disease groups because it provides more coverage to the vulva and the base of the penis.¹⁶

While preventive measures aimed at HSV seem to favor female sex, the disease has worse outcomes in women once it is contracted. Primary genital herpes lesions in women are more painful than in men, and are more often associated with systemic complications, including aseptic meningitis, autonomic nervous system dysfunction, development of extragenital lesions, and secondary yeast infections.^17- 18 In addition, vertical transmission in pregnant women can cause devastating effects in neonates.¹⁹

Research is aimed at preventing infections by diminishing the mucosal portal of entry. In vivo studies²⁰ of topical microbicides against vaginally and rectally transmitted HSV 2 found promising results of significantly reduced infection.

Human papillomavirus is a ubiquitous virus, with more than 100 types, 30 of which are sexually transmitted.²¹ The different strains can infect the genital area of men and women, including the skin of the penis, vulva, or anus and the linings of the vagina, cervix, or rectum. Most individuals who become infected with HPV are asymptomatic and clear the virus without any appreciable disease morbidity.²¹ Genital warts, which are benign, can be disfiguring and socially stigmatizing; certain high-risk strains of the viruses may cause abnormal Papanicolaou examination results in infected women. Ultimately, if exposed to other carcinogenic risks, these high-risk strains may also lead to cancer of the cervix, vulva, vagina, anus, or penis. Cervical cancer was predicted to cause 4000 deaths in women in the United States in 2004, with HPV identified as the main risk factor for development of the disease.²¹ Worldwide, more than 500 000 cases of cervical cancer will be diagnosed, killing 290 000 women per year.

Although HPV can cause anogenital cancer in men, it is significantly less common than cervical cancer.²² The physical barriers of external genitalia in men and women account for much of the sex differences in HPV infection. Smoking, more sexual partners, earlier age at sexual intercourse, high parity, lower socioeconomic status, poor genital hygiene, and coinfection with other diseases increase the likelihood of HPV infection progressing to anogenital carcinoma in women.^21,23- 25 In fact, smoking increased the risk of anal cancer linearly in premenopausal women but did not significantly affect the risk for men.²⁵ In addition, male circumcision decreases transmission of HPV in males but is less protective for women.²⁶ Female circumcision decreases the risk of HPV infection only if the entire clitoris is ablated. Partial circumcision of the clitoris afforded no substantial protection and was also associated with poor hygiene, infection, and earlier age at sexual intercourse.²³ While HPV infection is worsened by other STDs, early success in experimental animal models and clinical trials for an HPV vaccine^27- 31 provide hope that, in the near future, administration of vaccines will prevent HPV disease morbidity and mortality.

Women have a greater than 3 times higher rate of contracting chlamydia than do men,³² which may be due to the increased number of women who are screened for the disease. Chlamydia is generally an asymptomatic infection; therefore, it is less likely to be treated in early stages and can exert a great toll on infected women. Of untreated women, 40% develop pelvic inflammatory disease.³³ Pelvic inflammatory disease can lead to permanent damage of the female reproductive tract, including the fallopian tubes, uterus, and surrounding tissues, with chronic pelvic pain, infertility, and potentially a fatal ectopic pregnancy.^33- 37 Pelvic inflammatory disease can be devastating after only one episode. Of women with a single infection of pelvic inflammatory disease, 20% will experience chronic pain, 9% will have an ectopic pregnancy, and 8% will become infertile.³⁸ Pelvic inflammatory disease is responsible for 15% of all infertility.³⁹

The increased risk is due not only to the greater mucosal surface area present in women but also to the exposed squamocolumnar epithelium of the cervical os in female adolescents, which is less resistant to these pathogens.³⁹ In vivo studies²⁰ of topical microbicides against vaginal chlamydia found promising results of significantly reduced infection.

In approximately 50% of women infected with gonorrhea, the infection is asymptomatic and is not treated,⁸ again leading to sterility, pelvic inflammatory disease, and disseminated infections.^34- 37 Symptoms, when present, include increased vaginal discharge, dysuria, intermenstrual bleeding, and hypermenorrhea, with the most common local complication being acute salpingitis or pelvic inflammatory disease. Gonococcal perihepatitis (Fitz-Hugh-Curtis syndrome) can imitate acute cholecystitis⁸ and lead to misdiagnosis with failure to provide appropriate treatment. Women also have higher rates of oropharyngeal gonorrhea, which is usually asymptomatic and resolves spontaneously.⁸ Rectal gonorrhea is found in individuals who engage in receptive anal intercourse and in women who have endocervical gonorrhea and perineal contamination from vaginal secretions.

Trichomoniasis is an STD that infects approximately 7.4 million men and women each year.⁴⁰ The disease is caused by a protozoan parasite, Trichomonas vaginalis, and is usually asymptomatic in men but can cause minor irritation of the urethra. The disease may be asymptomatic in women as well but can cause a frothy yellow-green vaginal discharge with a pungent odor. Infection can also cause lower abdominal pain in rare cases.⁴⁰

Women are more physically susceptible to HIV infection than are men. Male-to-female HIV transmission during sex is about twice as likely to occur as female-to-male transmission.⁴¹ Women, who are more vulnerable to the disease's mucosal transmission,⁴² are exposed to higher concentrations of virus present in semen compared with the concentration present in vaginal fluid.⁷ According to the World Health Organization,⁴¹ millions of young people become sexually active each day, with no access to prevention services. In sub-Saharan Africa, three quarters of all 15- to 24-year-old persons living with HIV are female. Young women are 3 times more vulnerable to HIV infection than are their male counterparts, in part because of the use of sex as a bartering tool for money, food, and other basic necessities.⁴¹

While the risk of contracting HIV remains high for women, men continue to have higher rates of diagnosis overall because of the greater number of male intravenous drug users and homosexual men contracting the disease.⁴³ The epidemic is treated with antiretroviral therapy, but vaccine studies and topical microbicides show signs of promise for future use. Abner et al⁴⁴ found that a topical microbicide was effective in preventing HIV when applied to colorectal explant tissue, and early vaccine studies^45- 47 in animal models have shown enhanced humoral and cellular immune responses.

The presence of certain STDs can enhance an individual's susceptibility to other STDs and cause worsen disease manifestations. Contraction of HSV-2 makes individuals more susceptible to HIV infection and makes those who already have HIV more infectious.¹¹ An anogenital ulcerative disease, such as HSV, may increase the chances of transmitting HIV when an individual is infected with both. Herpes simplex virus infection increases this risk up to 5-fold because of the infiltration of CD4+ cells in the herpetic ulcers.⁴⁸ Studies⁴⁹ have indicated that coinfected individuals undergoing antiviral suppression therapy to combat HSV may respond more effectively to antiretroviral therapy.

Syphilis, which is also a genital ulcer disease, is associated with an increased risk of transmission of HIV because of the lack of an intact epithelial barrier in active syphilitic ulcers, increased numbers of macrophages and T lymphocytes with receptors for HIV, and the stimulation of macrophages by treponemal lipoproteins to up-regulate cytokine production.⁸ While syphilis is already known for its diverse presentations, infection in HIV-positive individuals produces higher rates of neurological manifestations and a greater incidence of ulcerative lesions in secondary syphilis.⁸ HIV-positive patients also require longer treatment for STDs than do immunocompetent patients.

The presence of chlamydia in an individual may cause the person to be up to 5 times more likely to contract HIV.³³ Gonorrhea infection also causes increased susceptibility to HIV infection in those who are HIV negative.⁵⁰ In addition, discharge of pus and mucus as a result of STDs such as gonorrhea or chlamydia infection also increases the risk of HIV transmission 3- to 5-fold.⁵¹ Trichomoniasis can cause genital inflammation in women, which increases their susceptibility to HIV infection and their ability to spread HIV if coinfected.^40,52 Human papillomavirus is a common STD in men and women, but is more common in women infected with HIV and more often associated with persistence and progression to malignancy in those who have HIV.⁵³

Sexually transmitted disease infections in women are able to infect neonates via vertical transmission. Neonatal transmission while in the womb or during childbirth can have devastating effects on the individual child and on the spread of disease, such as in HIV. In fact, the estimates of vertical transmission from mother to child are placed at 15% to 50% without anti-HIV treatment.⁵⁴ This transmission rate is particularly harmful in places such as sub-Saharan Africa, where three fourths of the population living with HIV is composed of young women with little access to costly antiretroviral drugs.⁴³

While neonatal HIV infection can be controlled but not cured, many other STDs passed to neonates can be cured with proper medication and even prevented with prophylaxis to the mother while pregnant. If proper medical care is not administered, effects can be disastrous. Neonates born to mothers with chlamydia are at risk for neonatal ophthalmia and pneumonia.³² Neonates who are exposed to gonorrhea in the vaginal canal may develop bilateral conjunctivitis or ophthalmia neonatorum. Prompt recognition and treatment are essential to avoid blindness.⁵⁵ Pregnant women with trichomoniasis may give birth to low-birth-weight neonates and may experience premature rupture of membranes and premature delivery.^40,52 Neonatal herpes infection can be life threatening and, although rare, can lead to long-term neurological impairment if not fatal.¹¹ Syphilis contracted in the womb causes a congenital syndrome with a wide spectrum of severity, with only severe cases clinically apparent at birth. An infant or child may have signs such as hepatosplenomegaly, rash, condyloma latum, snuffles, jaundice, pseudoparalysis, anemia, or edema. An older child may have stigmata such as interstitial keratitis, nerve deafness, anterior bowing of shins, frontal bossing, mulberry molars, Hutchinson teeth, saddle nose, rhagades, or Clutton joints.⁸

Pregnancy can also alter disease course in the mother. Pregnant women can expect an increase in HSV outbreaks as the immune system weakens.¹¹ To our knowledge, there is no evidence that HIV worsens in pregnancy, but inability to take some antiretroviral drugs during pregnancy may allow the disease to progress.

Women have economic and social inequalities that may put them at greater risk for STDs. A study⁴ of culture, sex, and social behavior in Cameroon showed that a woman's status had direct and indirect effects on the use of condoms. Issues such as age disparities between partners, practices of decision making, and openness of couples toward sexual discussion played a part in the decision to use or even discuss the use of condoms. Another study of sex inequalities in Vietnam showed that males and females had clear, and differing, sex roles and expectations. While Vietnamese society frowned on extramarital activities for women, men were less restricted and would engage in extramarital sex more often. When either partner showed signs or symptoms of STDs, both parties were reluctant to discuss it.⁵⁶

A similar study in Nairobi showed that even when aware of infections, partners were less willing to seek treatment for STDs because symptoms had ceased or their importance was downplayed or there was a lack of money. In addition, women waited longer than men to seek care and more women chose not to seek care because they were monogamous and did not relate their complaints to sexual intercourse.⁵⁷ Spanish investigators found similar sex inequalities contributing to a growing HIV epidemic. They found that economic dependence on partners; inability to access accurate health information on infection methods, prevention, or treatment; and sexual violence and discrimination all led to inequalities for women and higher risk factors for HIV transmission.⁵⁸

These reports accurately represent the growing epidemic of HIV infection in women⁴¹ and help elucidate why the world's deadliest STD continues to spread. Although the United States has comparatively lower numbers of HIV infection,⁵⁹ women in the United States continue to contract other STDs for reasons similar to those in other nations. A study⁶⁰ of 309 US college students showed that 34% of men and 48% of women interviewed did not use condoms. Barriers to use included how to talk to partners about use and the perception that a condom was not needed, especially for those who believed they were in a monogamous relationship.⁶⁰ Sex differences in US teenagers were exposed when researchers⁶¹ found that males knew more about correct condom use compared with their female counterparts. In 2004, the Global Coalition on Women and AIDS found that around the world, including the United States, access to care and treatment was more difficult for women. In the United States, this affected minority women and marginalized segments of the female population.⁴³

Much needs to be done to overcome the inequalities both sexes face in STD prevention, including education about transmission, barrier therapies, and the role of vaccination, and social and economic barriers to care. While both sexes experience these inequalities, women are more affected by the deadliest STDs, with dire consequences to their health and the health of their unborn children and fragmentation of the family and the makeup of societies in developing countries. Efforts centering on prevention of transmission must emphasize education and the social empowerment of women in societies worldwide. While the biological susceptibilities of women cannot be changed, prevention with barrier creams, female condoms, and vaccines offers hope to women in preventing disease morbidity and mortality. In the United States, males and females need better education to recognize the signs and symptoms of discharge diseases to prevent the loss of fertility. As HIV continues to spread in women and men, health care providers should urge patients who are seropositive to be tested for other diseases, especially HPV. Conversely, patients who are positive for any STDs should be counseled about their increased susceptibility of HIV contraction and should be offered HIV testing.

Correspondence: Vandana K. Madkan, MD, 6655 Travis St, Suite 820, Houston, TX 77030 (vmadkan@gmail.com).

Financial Disclosure: None.

Accepted for Publication: December 8, 2005.

Author Contributions:Study concept and design: Madkan, Sra, and Tyring. Acquisition of data: Madkan and Giancola. Analysis and interpretation of data: Madkan. Drafting of the manuscript: Madkan. Critical revision of the manuscript for important intellectual content: Madkan, Giancola, Sra, and Tyring. Administrative, technical, and material support: Giancola, Sra, and Tyring. Study supervision: Giancola and Tyring. All authors contributed significantly in the formation of this work and take full responsibility for the integrity of the data.