To mark Cervical Cancer Prevention Week, which runs until January 29, Dr Rachel Mackey offers an update on diagnosing, treating and preventing the condition

Cervical cancer is the eighth-most common female cancer in Ireland, with approximately 250 cases diagnosed each year. However, it is the second-most common cancer — after breast cancer — among the 15- to 44-year-old age group.

Every year in Ireland, approximately 90 women die of cervical cancer. In more recent times, the link between cervical cancer and the human papilloma virus (HPV) has been established and over 85 per cent of cases of invasive cervical cancer are caused by either type 16 or type 18 of HPV.

It is estimated that at any given time, approximately 11 per cent of the general female population are harbouring cervical HPV infection. The peak age range for the incidence of cervical cancer is 35-47 years.

Several factors have been identified as causing an increased risk in contracting HPV infection — these include sexual activity from a young age, multiple sexual partners and a history of previous sexually transmitted infections.

Other risk factors include smoking, a lack of or very infrequent cervical smears, HIV and other states of chronic immunosuppression.

Exposure to diethylstilboestrol (DES) also increases cervical cancer risk.

Unfortunately, cervical cancer has few symptoms or signs until at a more advanced stage. Early invasive cancer has no symptoms and the cervix appears normal on examination. Any abnormalities will only be identified by smear examination.

Symptoms associated with advanced disease include abnormal vaginal bleeding, dyspareunia, bloody vaginal discharge and pelvic pain.

Speculum examination may reveal a growth on the cervix which is friable, and bleeds easily.

Investigations
If the smear indicates severe dysplasia, then a colposcopy and biopsy should be done to confirm the presence of inva-sive cancer. Likewise, any suspicious lesion on the cervix is also biopsied. Once invasive cancer has been confirmed, the process of staging begins, which is essential to the choice of treatment pathway.

Staging involves examination under anaesthesia (EUA), which includes cystoscopy and rectosigmoidoscopy. Other procedures may include intravenous pyelogram (IVP), CT scan or MRI, abdominal ultrasound and chest x-ray.

The following stages are used to describe the progression of cervical cancer:

• Stage O: this is carcinoma in situ, i.e. no invasion beyond the epithelial layer of the cervix;
• Stage I: this ranges from being only visible microscopically, to being greater than 4cm but with no spread beyond the cervix. The five-year survival rate is 80-95 per cent;
• Stage II: this stage ranges from the tumour being 4cm up to invasion of the upper third of the vagina and the tissues adjacent to the cervix (parametria) but no metastases or spread to the pelvic side-wall. The five-year survival rate is 65-69 per cent;
• Stage III: this stage ranges from extension to the lower two-thirds of the vagina to ureteric blockage but no distant metastases. The five-year survival rate is 40-43 per cent;
• Stage IV: this stage ranges the spread to local organs such as bladder and rectum, to distant metastases in lung or liver. The five-year survival rate is 15-20 per cent.

Treatment options depend on the overall staging. A simple hysterectomy is indicated if there is minimal depth of inva-sion. Radical hysterectomy is usually indicated for stages IA, up to and including Stage IIA disease.

If the disease is more advanced than IIA, then radiotherapy — either external or brachytherapy (internal) — is used in conjunction with chemotherapy. The overall five-year survival rate is 57 per cent.

Abnormal smears
Several classification systems are used to describe abnormal smears or degree of dyskaryosis. These are the cervical intraepithelial neoplasia (CIN) system and, more recently, the Bethesda system — as introduced by the National Cervical Screening Programme. Both systems differentiate between mild and severe dyskaryosis and allow the smear-taker to either observe and repeat, or refer for colposcopy and verification of the degree of abnormality.

Certain types of HPV, primarily 16 and 18, are responsible for 85 per cent of all cervical cancer cases. It is recognised that most women will contract the virus at some stage in their lives.

It is understood that the majority of women who bec-ome infected with the virus will have cleared it spontaneously within two-to-five years. The prevalence of persistent HPV in women aged 14-59 is estimated to be 25 per cent, and for women with high-risk types such as 16, the risk of progression to precancerous lesions is 40 per cent over three-to-five years.

Colposcopy is indicated for a minority of women in whom high-grade lesions are detected on smears, or for whom there is evidence of disease progression or failure to regress to a more minor level of smear abnormality after a period of surveillance.

Long loop excisions of the transformation zone (LLETZ) are performed after colposcopic examination if the deg-ree of dysplasia is thought to be significant. This procedure is both diagnostic (the specimen is examined histologically and clear tissue margins confirmed) and curative in 95 per cent of procedures performed.

Cervical cancer screening
As you can see from the survival rates listed above, this is a difficult cancer to treat successfully. This is due to the asymptomatic nature of the disease until such a late stage. Therefore, to have a screening test which can detect it at such an early treatable point is enormously beneficial.

Cervical smears fulfil the criteria set out for a successful screening test. They can be done easily and inexpensively; there is an accepted treatment for the disease; early intervention has a better outcome than late intervention; and there is an early asymptomatic phase in the natural history of the disease.

The average age for the development of precancerous lesions is 25-35 and, therefore, to start a cervical-screening programme in this age group greatly increases the chances of early detection and the avoidance of invasive disease.

The National Cervical Screening Programme, CervicalCheck, has been in existence since September 2008 and aims to reduce the incidence of cervical cancer by 80 per cent.

The cervical cancer vaccine is recently developed, specifically to protect against HPV. It is intended to be administered to girls prior to their first sexual activity, although this is not a requirement for vaccination.

The vaccine is administered over a six-month period with three vaccinations required at zero, two and six months. There are very few known side-effects associated with the vaccine.

Based on the data so far, the vaccine confers almost 100 per cent protection against HPV. Gardasil, which was the vaccine used in the national vaccination programme for 12-year-old girls in 2010, also provides 100 per cent protection against HPV 6 and 11, which are responsible for 90 per cent of genital warts.
The role of routine cervical smears cannot be replaced completely by vaccination against HPV infection. It is still recommended that vaccinated women still continue to have cervical smears on a regular basis.

Despite the relatively low survival rates for invasive cervical cancer, the future for this particular disease looks promising. The introduction of HPV vaccination, in conjunction with a comprehensive National Cervical Screening Programme, should radically reduce the incidence of cervical cancer in the future.

We are all too aware of the difficult task of cancer prevention. Cervical screening and HPV vaccination are two highly effective prevention mechanisms.
It is our collective responsibility as doctors to implement them to the best of our ability, in order to protect young Irish women in the future.

• Dr Rachel Mackey, MRCOG, Women’s Health Clinic, Dun Laoghaire. See www.womenshealthclinic.ie or call (01) 230 0556.

Workplace exposure to plasticisers and pesticides may lower a woman’s fertility and increase her chances of having a lower-birthweight baby, researchers have found. They based their findings on 6,000 women during various stages of their pregnancy, with due dates between 2002 and 2006. The women were part of a long-term study tracking the health of their children from foetal development to young adulthood.

Each of the women was comprehensively assessed,  including physical examination, questionnaires and interviews, during which they were asked how long it took them to conceive and what paid work they had done.  They were also asked about the types of jobs and activities they had performed and a job exposure matrix was used to assess their working conditions, including physical workload and exposure to chemicals during pregnancy.

Their average age was 30 years, and 68 per cent said they had planned their pregnancy. Around half the women were of black or minority ethnic origin.

Among the 3,719 who provided information on time to conception, a period of six-to-12 months or in excess of a year was reported by 15 per cent and 10 per cent, respectively. Six months to conception is considered long. Around one in 20 had a preterm birth and just over 1 per cent gave birth before 34 weeks.

Some 15 per cent of babies weighed less than 3kg at birth and 5 per cent were deemed to be of low birthweight. Older age, lower educational attainment, ethnicity, and smoking and drinking all affected time to conception and birthweight. These are all known risk factors.

Physically demanding work did not affect fertility or birthweight. If anything, regular handling of loads weighing 5kg or more was associated with improved fertility and heavier babies at birth. But this finding could be the result of healthier women taking on these jobs, the study’s authors commented.

But women exposed to phthalates — substances used to make plastics more flexible — and pesticides were more than twice as likely to take six months or longer to conceive and to have lower-birthweight babies, although the overall numbers were small, said the authors.

Online edition of Occupational and Environmental Medicine:  http://press.psprings.co.uk/oem/december/oem46516.pdf

Screening is offered to women aged 25 to 60 and outside that age group in certain populations

Dr Elaine Burke and Dr Bryan T Hennessy outline the pathology of cervical cancer and the treatment methods for early- and advanced-stage disease.

Cervical cancer is a common cause of cancer death in women. It is a disease of young women, and it is estimated that each woman who dies of cervical cancer loses, on average, 25 years of life. Yet this is a disease that is highly preventable, with evidence to suggest that screening may reduce cancer incidence and mortality by 80 per cent.

Worldwide, figures show that about 500,000 new cases are diagnosed annually, with 275,000 deaths per year, which accounts for 10 per cent of female cancer deaths. In Ireland, there are on average 180 new cases a year and 73 deaths.

Deaths from cervical cancer have been increasing in Ireland by 1.5 per cent per year since 1978. This is in contrast to the UK, where deaths have been steadily declining since the introduction of a more stringent screening programme in 1988.
Aetiology and risk factors
Cervical cancer has been unequivocally linked with a sexually-transmitted virus, human papilloma virus (HPV). There are over 100 types of HPV, some 15 of which are oncogenic — most commonly types 11, 16 and 18. HPV 16 and HPV 18 cause approximately 70 per cent of cervical cancers worldwide.

About 10 per cent of women at any one time have an oncogenic HPV infection, but the majority of these resolve spontaneously over time and do not progress to cancer. In some women, however, chronic HPV infection results in cervical intraepithelial neoplasia (CIN) III, a high-grade lesion with severely atypical cells, which can be the precursor of cervical cancer and eventually invasive cervical carcinoma.

HPV subtype and persistence of infection play a major role in the progression of dysplastic lesions to invasive carcinoma. Environmental factors and immunosuppression also play a role.

As HPV is sexually transmitted, risk factors for cervical cancer include early age at first intercourse and multiple sexual partners. Smoking is another risk factor, with the increased relative risk for squamous cell carcinoma in smokers app-roaching 60 per cent. The oral contraceptive pill (OCP) has been linked with cervical cancer; however women taking the OCP would be likely to be more sexually active than others and to use condoms less regularly, thus increasing exposure to HPV.

Immunosuppression, particularly due to HIV, is ano-ther risk factor, with about one in five HIV-positive women developing high-grade HPV-associated disease over three years. Finally, women with three or more full-term pregnancies are at greater risk of developing cervical cancer.

CervicalCheck, the national screening programme for cervical cancer in Ireland, was introduced in September 2008, and has provided free smear tests to over 500,000 women (as of September 2008 to September 2010).

Screening is offered to women aged 25 to 60 and outside that age group in certain populations, including women who are post-transplant, HIV-positive or on renal dialysis. Approximately 85 per cent of smears taken between 2008 and 2009 were normal. Women with abnormal smears are generally referred for colposcopy.

There are two types of vaccine against HPV available, a quadrivalent (immunises against HPV 16, 18, 6 and 11) and bivalent (immunises against HPV 16 and 18).

Two large, randomised, double-blind, placebo-controlled trials have shown a reduction in the incidence of CIN II and more severe disease by 97 per cent for the quadrivalent vaccine and by 93 per cent for the bivalent vaccine. The quadrivalent vaccine is now on offer in Ireland to second-level students in first and second year.
Pathology and spread
Cervical intraepithelial neoplasia, or CIN, is a malignant lesion that is confined to the epithelium of the cervix and can be a precursor of cervical cancer. It is graded I-III, depending on level of dysplasia. Dysplasia is recognised by the presence of koilocytosis, or vaculoised (halo) cells and enlarged nuclei with features of atypia.

The Bethseda System simplifies this classification as low-grade and high-grade squamous intraepithelial les-ion (LSIL and HSIL). This also avoids the notion that progression from CIN I to CIN II and III is inevitable, when it is in fact quite rare.

There are four main steps in the development of invasive cervical cancer: infection of the epithelium at the transformation zone by oncogenic HPV; persistent infection; progression of persistently-infected epithelium to cervical precancer; and invasion through the basement membrane.

Some 90 per cent of invasive cervical cancers are squamous cell carcinomas. Adenocarcinomas account for about 10 per cent. Rare types include adenosquamous and aggressive small-cell carcinoma. Primary sarcomas and malignant lymphomas of the cervix have also been described. Squamous cell carcinomas usually arise in the transformation zone and tend to be poorly defined, granular eroding lesions. Adenocarcinomas tend to arise in the squamocolumnar junction and will often have a fungating polypoid or papillary appearance.

The major routes of spread are predictable, and form the basis of staging. Direct and lymphatic spread occur much earlier than haematogenous. The cancer can spread directly downwards, invading the vaginal vault, or laterally, beyond the paracervical tissues and towards the lateral pelvic wall.

Lymphatic spread is to the pelvic and para aortic lymph nodes, with a high incidence of nodal involvement, even in localised disease. Sites of blood-borne metastases include the lungs, liver and bone.

Cervical lesions are usually asymptomatic until they become invasive, when they present with symptoms such as vaginal bleeding and/or discharge. Low back pain, dyspareunia or abdominal pain indicate a bulky tumour. Urinary and rectal symptoms are suggestive of locally advanced disease.

The tumour is often visible on speculum examination. Exophytic tumours are often bulky and form large, friable growths, while infiltrative lesions are harder to detect. If disease recurs after treatment, a characteristic clinical syndrome occurs, with pelvic, back and buttock pain, bowel disturbance and unilateral leg oedema due to lymphatic and venous obstruction.

Investigations
A full history and physical examination are needed, inclu-ding vaginal examination and palpation for lymphadenopathy. Work-up includes routine bloods, a chest X-ray and CT or PET-CT, and a cervical biopsy or cone biopsy if cervical biopy is inadequate. An intravenous pyelogram and barium enema can aid with staging.

MRI is useful to outrule disease high in the endocervix.

The International Federation of Gynaecology and Obstetrics (FIGO) staging system is commonly used for staging cervical carcinoma. In stage I, the tumour is confined to the cervix and can be microinvasive (Ia) or grossly visible (Ib). In stage Ib1, the visible tumour is <4cm; in stage Ib2, it is >4cm.

A stage II tumour has exten-ded beyond the cervix but not into the lower 1/3 of the vagina or pelvic side wall. Stage IIa tumours do not involve the parametrium, whereas stage IIb tumours do.

If the tumour has reached the pelvic side wall or the lower 1/3 of the vagina, or has caused hydroenphrosis, it is classed as stage III. Extensive local infiltration or spread to a distant site (e.g. liver, lungs) indicates stage IV disease.

Management of early-stage disease (FIGO stage Ia and Ib1 and non-bulky IIa)

The primary treatment for early-stage disease is either surgery or radiotherapy. Current evidence indicates that both approaches have similar oncological outcomes, therefore the decision depends on a number of factors, including patient’s age, child-bearing plans, disease stage, comorbidities and risk of disease recurrence.

Surgery is generally preferred in younger women, as it has the added advantages of preserving the ovaries and there are fewer long-term complications. It also defines the true state of spread of the disease, allowing for more accurate overall planning of treatment.

Those at high risk of recurrence post-operatively would include women whose histology showed positive or close resection margins, positive lymph nodes and microscopic parametrial involvement. These women should receive adjuvant treatment.

Management of advanced disease (FIGO Stage IIb to IV)

The mainstay of treatment for this group is radiotherapy and brachytherapy with concomitant cisplatin-based chemotherapy. The volume of radiotherapy is critical, and guided by assessment of nodal involvement in pelvic and para aortic nodes.

For patients with pelvic and para aortic node involvement, extraperitoneal lymph node dissection should be considered, followed by extended-field radiotherapy, chemotherapy and brachytherapy.
Metastatic disease
For patients with distant metastases, primary treatment is usually cisplatin-based chemotherapy. Individualised radiotherapy may be offered for control of symptoms. In patients with recurrent disease in whom cisplatin was used, combination platinum-based regimens are preferred over single-agent chemotherapy.

Patients with metastatic disease are rarely curable, but chemotherapy can have a limited role in prolonging survival and improving quality of life in patients who are not candidates for extensive surgery or radiotherapy. There are no studies as yet comparing chemotherapy with best supportive care in this situation.

Targeted therapies
Recently, attention has turned to molecular-targeted therapies in the management of cervical cancer. This would include drugs such as bevacizumab, a monoclonal antibody which acts against vascular epithelial growth factor and thus inhibits angiogenesis in tumour cells. Other agents include the tyrosine kinase inhibitors such as sorafenib, which also have anti-angiogenic properties.

Cervical cancer is a disease that continues to affect Irish women. The mainstay of treatment in early-stage disease is either surgery or radiotherapy, with chemoradiotherapy being the primary treatment for more advanced disease.

Metastatic disease is rarely curable, but palliative chemotherapy may prolong life and improve quality of life.

Cervical cancer is unusual in that it has been unequivocally linked with a virus, human papillomavirus (HPV), for which there is now a vaccine available.

In addition, there is a nationwide screening service available for women aged 25-60.

Therefore, it is hoped that with the continuing success of these programmes, cervical cancer will be a disease that future generations will see with diminishing frequency.
References on request.

• Dr Elaine Burke, Department of Medical Oncology, Beaumont Hospital, Dublin 9.

• Dr Bryan T Hennessy, Division of Cancer Medicine, The University of Texas MD, Anderson Cancer Center.

Gary Culliton examines new clinical guidelines for ultrasound diagnosis of early pregnancy miscarriage.

Despite recent controversies about possible failures to carry out ultrasound tests in miscarriage cases, new guidelines do not make ultrasound mandatory in every case. There are some clinical situations when it may not be necessary to do an ultrasound, Prof Michael Turner, the National Clinical Lead for obstetric and gynaecology care, believes.

The new ‘Guidelines for Ultrasound Diagnosis of Early Pregnancy Miscarriage’ provide information relating to the diagnosis of early pregnancy loss, defined as a loss within the first 13 weeks of pregnancy.

It specifically addresses the ultrasound diagnosis of miscarriage and acknowledges that further improvements need to be implemented in clinical practices, staff training and hospital services.

The HSE and the Institute of Obstetricians and Gynaecologists (IOG) have developed the document for the management of early pregnancy loss.

The guidelines state that all maternity units should provide a dedicated outpatient early pregnancy assessment unit (EPAU) and that ultrasound machines should be of good quality, regularly maintained and serviced and checked for safety. In addition, sonographers should be formally trained in both transabdominal and transvaginal ultrasound — as both methods are complementary.

Publication of the guidelines was expedited in the aftermath of the incorrect ultrasound diagnosis at Our Lady of Lourdes Hospital, Drogheda, last year. Dozens of women contacted helplines last summer about other experiences of misdiagnosis in Ireland’s maternity hospitals.

Joint letter
A joint letter from Dr Tony Holohan, Chief Medical Officer at the Department of Health, and Dr Barry White, HSE National Director for Quality and Clinical Care, was sent last year to all public and private obstetric facilities, asking them to immediately implement new safety measures in suspected miscarriage cases.

“We in the maternity services are determined to avoid a recurrence of the events which came to light last year,” Prof Turner stated.

The HSE added that there was a “level of uncertainty” in ultrasound scanning, especially in the early stages of a pregnancy.

In certain circumstances it can occur that a woman can be advised that there is no foetal heartbeat and a further scan arranged. It is rare that this repeat scan would show a viable pregnancy.

Of over 70,000 births in Ireland each year, there are approximately 14,000 miscarriages.

The joint letter stated that the decision to use drugs or surgical intervention in women who have had a miscarriage diagnosed must be approved by a consultant obstetrician.

Early pregnancy units have been developed to provide co-ordinated care for women experiencing pain or bleeding in early pregnancy. The care should involve a multidisciplinary approach involving doctors, nurses, ultrasonographers, midwives and support staff.

Maternity units may alternatively assess patients with potential or actual miscarriage as emergencies via clinics, gynaecology wards, day-care, emergency departments or other mechanisms or facilities.

The RCPI’s Institute of Obstetricians and Gynaecologists said that it was introducing an ultrasound training module in early 2011 as a mandatory part of its Basic Specialist Training.

The HSE had undertaken to review cases over the past five years to determine the number of patients who were recommended drug or surgical treatment when a diagnosis of miscarriage had been made in error, and where subsequent information demonstrated that the pregnancy was viable.

These guidelines are intended to be primarily used by health personnel working in the area of early pregnancy, which includes obstetricians, midwife sonographers, radiographers, radiologists and general practitioners.  All of the groups should be familiar with the various diagnostic tools necessary to help delineate a viable from a non-viable pregnancy.

Prof Turner is also working with the Institute of Obstetricians and Gynaecologists and other parties to develop a training programme in obstetric ultrasound for all healthcare professionals providing early pregnancy care thoughout the country.

The guidelines will be implemented through local implementation boards that are being set up in each of the 19 maternity units around the country. Each implementation board has been given until the end of April to develop an implementation plan in line with these guidelines.

Pregnant mums who regularly use mobile phones may be more likely to have children with behavioural problems, particularly if those children start using mobile phones early themselves, suggests research published online in the Journal of Epidemiology and Community Health.

The researchers based their findings on more than 28,000 seven-year-olds and their mothers who were part of the Danish National Birth Cohort (DNBC) study, which enrolled nearly 100,000 pregnant women between 1996 and 2002, and tracked their children’s long-term health.

The mothers supplied detailed information on their lifestyle, dietary and environmental factors during the course of four lengthy phone interviews during and after pregnancy. When their children reached the age of seven, the mums were quizzed again about their and their children’s  health, including behaviour, which were scored using validated assessments. They were also asked to provide details of their mobile phone use during pregnancy and their children’s mobile phone use.

The researchers had already studied a group of mothers and their 13,000 children from the DNBC and found similarities between the two groups.

In the new group, more than 35 per cent of the seven-year-olds were using a mobile phone compared with 30 per cent of the previous group. In both groups, around 3 per cent of children were considered to have borderline behavioural problems, and similar proportions were categorised as exhibiting abnormal behaviour. Children in both groups exposed to mobile phones before and after birth were 50 per cent more likely to have behavioural problems.

Journal of Epidemiology and Community Health, Online First 2010; doi: 10.1136/jech.2010.115402.

Babies with mothers who receive influenza vaccines while pregnant appear less likely to be infected with flu in their first six months of life, according to a new report.
The report followed a study of a non-randomised observational cohort of children on Navajo and White Mountain Apache Indian reservations, where children have a higher rate of severe respiratory infection than the general population.

A group of 1,169 women who delivered babies during one of three influenza seasons completed questionnaires about demographics, vaccination status of all family members and flu risk-factors. A total of 1,160 mother-infant pairs then gave blood samples that were assessed for flu antibody presence. Mothers completed a second questionnaire at the end of the flu season and surveillance was conducted throughout to track new influenza-like illnesses.

During the flu season following their birth, 17 per cent of infants were hospitalised for influenza-like illness, 36 per cent had only an outpatient visit for a respiratory cause and 48 per cent had no flu or flu-like episodes. Infants whose mothers were vaccinated had a 41 per cent lower risk of laboratory-confirmed influenza virus infection and a 39 per cent reduced risk of hospitalisation from influenza-like illness.

In addition, those with blood samples available had higher levels of flu antibodies at birth and at two-to-three months than babies born to unvaccinated women.

“Although influenza vaccination is recommended for pregnant women to reduce their risk of influenza complications, these findings provide support for the added benefit of protecting infants from influenza virus infection up to six months, the period when infants are not eligible for influenza vaccination but are at highest risk of severe influenza illness,” they concluded.

Early online version of Archives of Pediatrics and Adolescent Medicine, available at www.jamamedia.org.

Women whose mother suffered from hyperemesis gravidarum are three times more likely to suffer from the extremely serious and severe form of morning sickness, Norwegian researchers have found. The team from the Norwegian Institute of Public Health noted that hyperemesis was previously thought to be caused by psychological issues, “such as an unconscious rejection of the child or partner.”
Against that background, the researchers investigated the records of 2.3 million births from 1967-2006.

The authors studied hyperemesis gravidarum patterns in more than 500,000 mother-and-daughter units and almost 400,000 mother-and-son units.
The results showed that if a mother had hyperemesis, her daughter was three times more likely to develop the condition. However, there was no increased risk to the female partners of sons whose mothers had suffered from the illness.
From their findings, the researchers concludes that the study provided a new perspective about the causes of hyperemesis and “a better understanding of the psychological consequences of experiencing severe nausea and vomiting could be helpful for clinicians who treat and counsel women with hyperemesis gravidarum.”
They added that “it is possible that the risk is caused by environmental factors that are shared by mothers and daughters.”
BMJ Online, available at http://www.bmj.com/cgi/doi/10.1136/bmj.c2050 and http://www.bmj.com/cgi/doi/10.1136/bmj.c2178

Twice-weekly injections of the hormone kisspeptin may provide a new treatment to restore fertility in some women, according to research presented last month at the Society for Endocrinology BES meeting in Manchester.
The findings show that twice-weekly injections can lead to increases in the levels of sex hormones, which control the menstrual cycle. This is the first study to show this effect can be maintained over the long term and it may lead to new therapies for women whose infertility is due to low sex hormone levels.

Kisspeptin is a product of the KISS-1 gene and is a key regulator of reproductive function. Animals and humans lacking kisspeptin function do not go through puberty and remain sexually immature.
A team led by Dr Waljit Dhillo of Imperial College London studied women with a condition called hypothalamic amenorrhoea, where a deficiency in sex hormone levels prevents menstruation, resulting in infertility.
Previously, Dr Dhillo’s group found that a one-off injection of kisspeptin caused an increase in sex hormone production in these women, but further daily administration was not effective as the system stopped responding.
The aim of the present study was to examine kisspeptin’s potential as a fertility treatment by finding a dose regimen that would maintain sex hormone production over a sustained period of time.
Over eight weeks, a group of ten women with hypothalamic amenorrhoea were either given twice-weekly injections of kisspeptin (n=5) or twice-weekly injections of saline as a control (n=5).
Blood samples were taken at regular intervals to measure their levels of luteinising hormone (LH) and follicle stimulating hormone (FSH). Women demonstrated a large increase in circulating sex hormones on day zero (mean maximal LH increase 21.5IU/l), which was halved to 10.0IU/l on day 14.
However, after day 14, their responsiveness to the kisspeptin treatment remained steady. On the last day of the trial, women who had been given kisspeptin injections showed a 16-fold increase in their hormonal response, compared to the saline controls.
This is the first long-term clinical study to examine the effectiveness of kisspeptin treatment. Twice-weekly injections of kisspeptin, administered over a two-month period, can successfully stimulate the release of sex hormones in women with infertility due to hypothalamic amenorrhoea and this treatment does not cause any side-effects. These findings now need to be confirmed in large-scale randomised trials, before any treatments can be brought into clinical practice.

Consultant Physician and Endocrinologist Dr Mary Ryan examines the diagnosis and treatment options for polycystic ovary syndrome

Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in women, accounting for between 7 per cent and 10 per cent of presentations, and is a major cause of infertility. PCOS can present in any age during the reproductive years. Due to its often-vague presentation, it can take years to reach a diagnosis.
Other names for this syndrome include polycystic ovary disease (PCOD), functional ovarian hyperandrogenism, Stein-Leventhal syndrome (original name, not used in modern literature), ovarian hyperthecosis and sclerocystic ovary syndrome.
The condition was first described as a syndrome in 1935 by Stein and Leventhal. The principal features are obesity, anovulation (resulting in irregular menstruation or oligomenorrhea), acne, enlarged ovaries and excessive amounts or effects of androgenic (masculinising) hormones, which can lead to hirsuitism.
The symptoms and severity of the syndrome vary greatly among women. While the causes are unknown, insulin resistance, diabetes and obesity are all strongly correlated with PCOS. The symptoms vary in severity from subject to subject.
Definition
The following are diagnostic criteria of PCOS:
l Chronic anovulation;
l Clinical (acne hirsutism); or
l Biochemical (elevated androgen level) and evidence of hyperandrogenism.
These features were required to make the diagnosis of polycystic ovary syndrome. However, the most recently revised criteria, by the Rotherham Polycystic Ovarian Syndrome Consensus Group in 2003, have revised these and two of the following are now sufficient for establishing the diagnosis:
l Oligomenorrhea or anovulation;
l Clinical or biochemical evidence of hyperandrogenism;
l Polycystic ovary disease.
Ultrasound criteria that were considered specific and sensitive in defining PCOS include the presence of 12 or more follicles in each ovary, measuring 2mm to 9mm in diameter, and increased ovarian volume and stroma. Only one ovary with these criteria is sufficient. These ultrasound criteria do not apply to women on the contraceptive pill.
Women with PCOS are at risk for the following:
l Endometrial hyperplasia and endometrial cancer (cancer of the uterine lining) are possible, due to overaccumulation of uterine lining, and also lack of progesterone resulting in prolonged stimulation of uterine cells by oestrogen. It is however unclear if this risk is directly due to the syndrome or from the associated obesity, hyperinsulinemia and hyperandrogenism;
l Insulin resistance/type II diabetes;
l High blood pressure;
l Dyslipidemia (disorders of lipid metabolism — cholesterol and triglycerides);
l Cardiovascular disease;
l Strokes;
l Weight gain;
l Miscarriage;
l Acanthosis nigricans (patches of darkened skin under the arms, in the groin area or on the back of the neck);
l Autoimmune thyroiditis.
Although a pelvic ultrasound is a major diagnostic tool, it is not the only one.
Standard diagnostic assessments include: history-taking, specifically for menstrual pattern, obesity, hirsutism and absence of breast discharge; gynaecologic ultrasonography, specifically for small ovarian follicles; laparoscopic examination (which may reveal a thickened, smooth, pearl-white outer surface of the ovary); and serum levels of androgens, including androstenedione, testosterone and dehydroepiandrosterone sulfate, which may be elevated.
Some other blood tests are suggestive but not diagnostic, such as luteinizing hormone (LH), follicle stimulating hormone (FSH) and sex hormone binding globulin.
Exclusions
Obviously it is important to exclude other aetiologies such as androgen secreting tumours, Cushing’s syndrome and non-classical congenital adrenal hyperplasia.
The pathophysiology remains unknown. A prominent characteristic syndrome is that the reproductive (hyperandrogenemia, anovulation) and metabolic (insulin resistance, obesity) disorders co-exist, to the degree that it is unclear which are primary.
No single aetiological factor can account for the whole spectrum of abnormalities seen in PCOS. Increased frequency of hypothalamic release of gonadotropin-releasing hormone (GnRH) is found in women with polycystic ovarian syndrome. It is unclear whether this defect in GnRH post generation is a primary or a secondary abnormality.
Increased frequency of GnRH favours the increasing of LH versus FSH from the anterior pituitary, so that LH causes increased infrequency and amplitude. Therefore, anyone would see an elevated LH to FSH in most women.
The ovary in polycystic ovary syndrome responds to LH stimulation with the preferential increase in the production of androgen versus oestrogen. Estradiol levels are typically normal to low, but oestrone levels are significantly elevated. This is because of a conversion of androstenedione and oestrone tissue, which further stimulates LH and suppresses FSH.
Hyperinsulinemia is a feature of polycystic ovary disease and this observation was first made in 1980. Before this, the observation was made that women with syndromes of extreme insulin resistance also had hyperandrogenemia and anovulation.
Insulin and insulin-like growth factor can impact several of the pathways that contribute to the pathogenesis of polycystic ovarian syndrome. Insulin decreases the synthesis of sex hormone binding globulin, the effect of which would be to increase androgen bioactivity.
A direct role of insulin in the production of adrenal androgens in the hypothalamic pituitary gonadal axis disorder has been proposed. There is evidence to suggest that PCOS is heritable, but the pathogenesis of the syndrome points to a complex multigenic disorder. Candidate genes that may be responsible for alterations of ovarian, hypothalamic and insulin receptor function have been the focus of linkage and case control studies.
Infertility and obesity
Women with polycystic ovary syndrome may ovulate intermittently and it therefore takes longer for them to conceive. If pregnancy does occur, there is an increased risk for pregnancy-induced hypertension, pre-eclampsia, gestational diabetes, pregnancy loss and preterm labour.
A subset of women with polycystic ovary syndrome has persistent anovulation and infertility.
Central obesity affects 40 per cent to 50 per cent of women with polycystic ovary syndrome. Interestingly, the main body mass index for women with PCOS in the United States is between 35 per cent and 40 per cent.
In Europe and other countries, this is between 25 per cent and 28 per cent, or less.
Obesity is not considered a triggering event in the development of polycystic ovary syndrome, but it is an independent risk factor for reproductive and metabolic complications. The increased waist-to-hip ratio that is associated with higher risk for insulin resistance and development of type II diabetes has been noted in both obese and lean women with polycystic ovary syndrome.
Insulin resistance and hyperinsulinemia can be present even in the absence of obesity, but these conditions are exasperated by the presence of it. Severe insulin resistance is usually appreciated clinically by the presence of acanthosis nigricans.
Many women may have a mild form with slightly elevated fasting serum insulin levels.
Reducing insulin resistance by weight loss or pharmacological means, such as with metformin or thiazolidinediones, can be associated with increased ovulation and lower androgen levels — thereby suggesting an important role for insulin resistance in the pathogenesis for this disorder.
Treatment
The treatment of women with polycystic ovary syndrome should be individualised to the patient and can involve both non-pharmacological and pharmacological approaches. There are several treatment options for each of the manifestations of PCOS.
Most manifestations can be reversed by improving insulin resistance either by weight loss or pharmacological therapy. Typical response to therapy is slow, with clinical changes lagging behind chemical improvement by several months.Pregnancy should be excluded before initiating pharmacological therapy with oral contraceptives or anti-androgens. Weight loss should be the first line of therapeutic option in all women who are overweight and obese.
Weight loss of greater than 5 per cent of body weight has been shown to decrease testosterone levels, improve hirsutism, increase sex hormone-binding globulin, improve menstruation and ovulation and increase pregnancy rates.
Hirsutism can be treated by removing the hair by bleaching, waxing or laser treatment, but obviously anti-androgens can also help in this regard. Enflornithine hydrochloride cream (Vaniqa), which slows hair growth, can be used to treat facial hirsutism. Insulin sensitisers can reduce insulin and androgen levels and increase ovulation.
Clomiphene citrate has been shown to be superior to metformin in achieving contraception, but has a risk of multiple pregnancies. Finasteride, which blocks conversion of testosterone to dihydrotesterone, can be used to treat hirsutism. Because of the teratogenic potential of anti-androgens, they must be used in women who have been treated with effective contraception.
Long-term risks for CVD
Long-term metabolic and cardiovascular disease (CVD) associated with PCOS heightens the importance of a proper diagnosis. The prevalence of impaired glucose tolerance and type II diabetes increase in women with polycystic ovary syndrome (where there is a three-to-seven times higher risk of developing diabetes).
This association is seen in both obese and lean women with polycystic ovary syndrome. Patients with a family history of type II diabetes are at an even greater risk of developing diabetes.
Studies have shown that a longer irregular menstrual cycle can mean a twofold increase in the risk of hypertension in women with polycystic ovary syndrome. The development of hypertension increases dramatically by the time of perimenopause. Women with PCOS are also at increased risk of developing dyslipidemia and they have also been shown to have abnormal vascular function and an increased risk of inflammation.
Whether women with polycystic ovary syndrome and metabolic syndrome are at increased cardiovascular risk remains a question for future investigation, although predictions of a sevenfold risk for myocardial infarction have been made.
l Dr Mary Ryan,
Consultant Physician & Endocrinologist,
Barrington’s Hospital,
Georges Quay, Limerick.
Aut Even Hospital,
Freshford Road,
Kilkenny

Women who have ever used the oral contraceptive pill are less likely to die from any cause, including all cancers and heart disease, compared with ‘never users’, researchers have claimed.
The results of a new study show a slightly higher risk in women under 45 years old who are current or recent users of the pill. The authors stress that the effects in younger women disappear after about ten years.

Furthermore, the benefits in older women outweigh the smaller excess risks among younger women.
The study continues to find a higher rate of violent or accidental death among oral contraceptive users compared with never users. The authors are unable to explain this persistent finding.
In May 1968, the Royal College of General Practitioners (RCGP) began the RCGP Oral Contraception Study, one of the world’s largest continuing investigations into the health effects of oral contraceptives.
Early reports from the RCGP study suggested an increased risk of death among oral contraceptive users, mainly due to an excess of strokes or other vascular problems among older women or those who smoked. Although a later report suggested that these effects disappear once the pill is stopped, at the time there were relatively few cases of different types of cancer.
These latest results, led by Prof Philip Hannaford from the University of Aberdeen, relate to the 46,000 recruited women, followed for up to nearly 40 years, creating more than a million woman-years of observation.
The results show that in the longer term, women who used oral contraception had a significantly lower rate of death from any cause, including heart disease and all cancers (notably bowel, uterine and ovarian cancers) compared with never users.
This equates to 52 fewer deaths per 100,000 woman-years. Slightly higher rates were found among younger women who had used oral contraception, with 20 more deaths per 100,000 among those younger than 30, and four more deaths per 100,000 among 30-39 year olds.
But by the age of 50, the benefits outweighed these modest risks, with 14 fewer deaths per 100,000 among 40-49 year olds; 86 fewer deaths per 100,000 for 50-59 year olds; 122 fewer deaths per 100,000 for 60-69 year olds; and 308 fewer deaths per 100,000 for 70+ year olds.
“Many women, especially those who used the first generation of oral contraceptives many years ago, are likely to be reassured by our results,” commented Prof Hannaford.
“However, our findings might not reflect the experience of women using oral contraceptives today, if currently available preparations have a different risk than earlier products.”
The authors conclude that their results, derived from a relatively healthy UK study group, show that oral contraception is not significantly associated with an increased long-term risk of death — indeed, a ‘net benefit’ was apparent.
However, they point out that the balance of risks and benefits may vary globally, depending upon patterns of oral contraception usage and background risk of disease.
BMJ 2010;340:c927.