Tales from the clinic

A tale of twos - With a focus on premature ovarian insufficiency

Two countries/two services/two cases from each

These tales from the clinic focus on cases from primary care and from a tertiary referral service in secondary care. The cases from secondary care describe less common conditions, but for all women with lack of estrogen, irrespective of the underlying cause, management in a specialist service offers the benefits of a multi-disciplinary team approach, including psychological support.

We hope to raise awareness of all potential causes of estrogen deficiency in younger women, including those with POI and the potential benefits associated with early recognition and treatment. POISE, a long-term, NIHR funded, multicentre UK study, aims to determine whether the combined pill or hormone replacement therapy, has the best impact on bone health (primary outcome) in women with premature ovarian insufficiency (POI). It is due to commence very soon.

Premature ovarian insufficiency refers to ovarian failure resulting in hypoestrogenism and amenorrhoea before the age of 40. The incidence is estimated to be between 1.1% to 3.7%, although this may be an underestimate, due to reliance on self-reporting.^1–3 There is no doubt that in practice, POI is under diagnosed, despite excellent guidelines and toolkits.^4–6 This can lead to poor health outcomes and a significant adverse effect on quality of life.^7,8

Two cases from Dr Karen Soffe, a GP with a special interest in Women’s Health from the Republic of Ireland:

I am a GP working in a small town in the west of Ireland. I have been working to improve my skills in the management of women through their post reproductive years for many years now. I set up a menopause clinic 5 years ago and am currently working towards validating this work by gaining the advanced PPMC certification.

One of the more frustrating aspects of establishing a menopause service has been the number of women presenting in their 50’s with osteoporosis, severe urogenital atrophy, mental health issues and a high risk of cardiovascular disease. These women have in fact untreated premature ovarian insufficiency.

The under diagnosis of POI in Ireland is exacerbated by several factors. Infertility services are largely provided by private clinics who operate on a self-referral basis and GPs are often unaware that patients have had fertility treatment. This is particularly true of women using egg donation. There is often no follow up provided for patients and as they do not require contraception, this potential clinical interaction with their general practitioner is also lost.

Cancer care in children is provided by either one of two stand-alone tertiary service level paediatric hospitals. The clinical records of survivors of childhood cancers over time may be lost as a result of relocation and changing GPs. Sometimes patients don’t even disclose it as part of their past medical history. Historically, an entire generation of GP’s had a negative opinion of Hormone Replacement Therapy (HRT) and very little experience of prescribing it. As a result, many of these women, even if they had presented, would have had poor advice regarding HRT as a treatment option.

These two anonymised cases, described with the patients consent, highlight some of the difficulties experienced by patients and the potential patient benefits to be gained by better education of General Practitioners and the wider primary health care team.

LW, a 35-year-old type 1 diabetic, presented to me with an acute medical issue while I was providing emergency cover in another clinic. As part of the medical history, I asked her the date of her last menstrual period. She said she had been amenorrhoeic for over 10 years. I noted from her file that she had had two previous FSH levels >35 IU/l, as part of routine bloods, dating back seven years. On further discussion she told me that she had been referred to a gynaecologist ten years previously, when her periods had stopped and was prescribed the combined pill (COC). She was under the impression that this was to “regulate her periods”. Shortly afterwards, she was diagnosed with type 1 diabetes and sent to see an endocrinologist, who advised her to stop the pill, as it was unsafe in people with diabetes (although UKMEC 2). As she was not in a relationship and not in need of contraception, she stopped her pill and thought no more about it. She had never heard of POI and was unaware of the potential effects of long-term lack of estrogen. I sign posted her to “Information for women with Premature Ovarian Insufficiency”, provided by ESHRE and subsequently discussed her case with her own GP and arranged further investigations, treatment and follow up as per the ESHRE guidelines. ⁹

SH is a 34-year-old mother of two. She was diagnosed with a locally advanced colorectal cancer in 2019. Her treatment included long course, neoadjuvant chemo and radiotherapy, followed by excision surgery and a colostomy. Her oncologist did raise the possibility of her therapy affecting her ovarian function, but as she assured them that she considered her family was complete, there was no further discussion regarding potential health risks or advice regarding hormone replacement therapy. I flagged her file early on in her therapy to remind us to discuss the benefits HRT in the context of POI. Shortly after her surgery we discussed the symptoms she might expect and possible treatments and long-term benefits thereof and gave her written information. She re-presented six months later with flushes, amenorrhoea, low energy, poor sleep, new onset anxiety and “an inability to cope”. The combined pill was not a treatment option due to her high BMI (UKMEC 3). Her pelvic surgery left her with a chronically discharging fistula between the site of her perineal drain and her bladder, so I felt that an intrauterine system was best avoided, until this problem had resolved. She is now very well on 100 mg estradiol patch and desogestrel, 150 mcg daily (off licence), to provide her with endometrial protection and contraception. She tells me that she would have put her symptoms down to her cancer treatment and not presented for help had she not been forewarned and well informed of the options and potential benefits of treatment.

These two women represent the tip of the iceberg in relation to the under diagnosis and consequent lack of treatment of women with POI. It is my goal to play my part in improving outcomes. I believe this requires improving awareness among the female population and education of primary health care teams including trainees. We need as many healthcare providers as possible, who are in regular contact with this group of women, to ask the right questions to screen for POI. To this end I am currently doing a survey, using a simple questionnaire, given to all women between the ages of 25 and 40, presenting for cervical screening. If this proves successful, then once validated, it could be a simple, cost-effective way of screening for POI.

Two anonymised cases, discussed with the patients consent, from Dr Cara Williams, Consultant Paediatric Gynaecologist, Liverpool Women’s NHS Foundation Trust and Alder Hey Children’s Hospital.

Differences in Sex Development (DSD) refers to a group of conditions where the anatomical, chromosomal or gonadal sex is atypical. It is estimated that genital anomalies occur in 1: 4500 live births. DSD can be subdivided into three groups: 46XX DSD, 46XY DSD and Chromosomal DSD. ¹⁰ Girls with DSD can present at any time from birth into adolescence and even early adulthood. DSD conditions fall under the broader umbrella of Congenital Gynaecological Anomalies (CGA), which also encompasses the complex Mullerian Duct Anomalies. NHS England CGA service specification covers the provision of specialised, MDT gynaecological management, for girls and women with rare, congenital anomalies of the female genital tract. ¹¹

I am a Consultant Gynaecologist with a special interest in Paediatric and Adolescent Gynaecology, based at Liverpool Women’s Hospital. We provide a multidisciplinary adult CGA and Turner’s Syndrome clinic. In addition, I lead the Paediatric Gynaecology and DSD service at Alder Hey Children’s Hospital. Recently, I started a monthly general menopause clinic and am working towards the advanced PPMC certificate.

These two cases are taken from my adult CGA clinic, and they highlight some of the rarer causes of POI, requirements for hormonal treatment, and the importance of multidisciplinary working within a specialist centre.

Case 1

JG is a 17-year-old, diagnosed with Complete Androgen Insensitivity Syndrome (CAIS) at the age of five, when she presented with bilateral inguinal hernias, and a subsequent karyotype confirmed 46XY. The inguinal hernias were repaired and the gonads left in situ. She went through spontaneous puberty with good breast development, due to aromatisation of testosterone to oestrogen. At the age of 15, she underwent a laparoscopic bilateral gonadectomy, due to the small risk of malignancy in the intra-abdominal gonads. ¹² At the time of the laparoscopy, she was found to have a 4 cm blind ending vagina and absent uterus. Following the gonadectomy, she was commenced on Progynova 2 mg daily, but despite this she had low energy levels and her hair was falling out. She was referred for vaginal dilation therapy.

At 16 years of age, she was transferred to the adult CGA clinic. Her treatment was changed to Evorel 50 patches by her GP, but she did not like wearing patches, so started taking Progynova orally again. On review in the adult CGA clinic, she was changed to Oestrogel 2 pumps daily, to be gradually increased to 4 pumps daily. The plan was to achieve adequate oestrogen levels and then review her with a view to adding testosterone gel. This has been shown to be effective in adult women with CAIS following gonadectomy. ¹³ She completed vaginal dilation therapy and is now sexually active without any problems. BMD has shown mild osteopenia of the lumbar spine. She was seen by clinical health psychology within the DSD team at Alder Hey Children’s Hospital but did not really engage much at the time. She now feels ready to talk about her condition and has been referred to clinical health psychology within the adult CGA team.

Case 2

OM was referred by the fertility clinic to the adult CGA service at the age of 30. She was diagnosed with 46XY, pure gonadal dysgenesis (Swyer Syndrome), at the age of 15, when she presented with delayed puberty. She had bilateral gonadectomy at the time of diagnosis, due to the high risk of gonadal malignancy. ¹⁴ At the time of the gonadectomy, she was found to have a pre-pubertal uterus and vagina. Following induction of puberty, she was commenced on Kliofem (2 mg E2/1 mg Norethisterone). She did not engage with the service when she was younger and was therefore lost to follow up for many years.

When she was seen in the adult CGA service, she had been having bleeding on Kliofem. Hysteroscopy and biopsy, organised by the fertility clinic, was normal. She was also very tired and struggling with weight gain. She was switched to Femoston 2/10, which gave her regular withdrawal bleeds and she felt much better in herself. She started going to the gym and lost 2 stone in weight. She was referred for a BMD scan, which was normal.

She was seen by clinical health psychology in children’s services but did not like to talk about her condition and did not engage with the support offered. She has never spoken to anyone about her condition. She was referred to clinical health psychology within the adult CGA service, but this was put on hold as she was focusing on fertility treatment. She has had IVF with donor eggs and donor sperm, as a single parent, and she is currently 9 weeks pregnant.

These 2 cases involve rare conditions, which need long term specialist multidisciplinary care. They highlight the importance of robust specialist transition pathways, from children’s to adult services, as this is a time when disengagement from services can be high, and a time when psychological support is paramount.