Investigating infertilityBMJ 2009; 339 doi: http://dx.doi.org/10.1136/bmj.b3390 (Published 09 September 2009) Cite this as: BMJ 2009;339:b3390
- Vaidyanathan Gowri, assistant professor, obstetrics and gynaecology,
- Rajeev Jain, associate professor, radiology
- Correspondence to: V Gowri
A 23 year old woman was referred to the infertility clinic for subfertility and an ovarian tumour. She had been married for two years and reported having irregular periods every two or three months. She also had a history of mild dysmenorrhoea. She reported having gained 16 kg after marriage and developing excess growth of fine hair all over her body and face. She did not have galactorrhoea, acne, altered appetite, or thyroid symptoms. Apart from treatment for infertility (ovulation induction with clomifene citrate) her medical history was unremarkable. There was no family history of diabetes or hypertension.
On examination she was moderately built with a body mass of index of 26 and normal secondary sexual characters. She had a slight excess of fine hair on her face and abdomen. Examination of the breasts and thyroid was normal. No masses were found on examination of the abdomen, and on bimanual examination the uterus was normal with no adnexal masses.
A routine transvaginal scan in the outpatient clinic showed bilateral polycystic ovaries with a 4 cm complex cystic lesion in the left ovary (possibly a dermoid cyst) and minimal free fluid in the pouch of Douglas.
1 How would you approach this consultation?
2 What imaging investigations would be useful?
3 Would metformin help improve her fertility?
1 Investigate infertility by taking a detailed history for both partners and performing semen analysis in the man. In the woman, irregular menstrual cycles, hirsutism, and suspected polycystic ovaries warrant hormonal investigations. Measure follicle stimulating hormone, luteinising hormone, testosterone, thyroid function, and prolactin to establish the cause of irregular periods. Request tumour markers in view of the free fluid and the complex mass in the left ovary.
2 Large and complex cystic lesions in premenopausal women require follow-up sonography or physical examination to assess for interval decrease in size. The most common persistent lesions in premenopausal women are dermoids and endometriomas, although malignancy should be ruled out. Magnetic resonance imaging may provide a diagnosis in persistent complex masses.
3 Metformin as a primary treatment in polycystic ovary syndrome does not improve fertility.
Hirsutism, obesity, and irregular periods fit with a diagnosis of polycystic ovary syndrome in this patient. The Rotterdam European Society for Human Reproduction and Embryology (ESHRE) and the American Society of Reproductive Medicine (ASRM) polycystic ovary syndrome consensus workshop group has suggested a broader definition, with two of the three following criteria being diagnostic of the condition.1
Polycystic ovaries: either 12 or more peripheral follicles or increased ovarian volume (greater than 10 cm3)
Oligo-ovulation or anovulation
Clinical or biochemical signs of hyperandrogenism.
A raised luteinising hormone or follicle stimulating hormone concentration is no longer a diagnostic criterion for the syndrome because of its inconsistency.2 Recommended baseline investigations to rule out other causes of irregular periods are to measure testosterone, free androgen index, thyroid function, and prolactin.2 In cases of clinical evidence of hyperandrogenism and total testosterone greater than 5 nmol/l, 17-hydroxyprogesterone should be sampled and androgen secreting tumours excluded. If Cushing’s syndrome is suspected, this should be investigated according to local practice.2
Tumour markers, such as CA 125 for epithelial malignancy, should be requested because of the free fluid and adnexal mass. Serum CA 125 concentrations of 30 U/ml or more may be indicative of malignancy,3 although various cut-off values have been used (for example, ≥35 U/ml in postmenopausal women and ≥65 U/ml in premenopausal women).4 5 6 7 8 Serum CA 125 concentrations can also be misleading—results may be falsely positive in women with conditions that affect the peritoneal surface, such as endometriosis and pelvic infection.9 10 Because epithelial ovarian malignancy is rare in this age group, other tumour markers, such as α fetoprotein, lactate dehydrogenase, and serum β human chorionic gonadotrophin, should be investigated to rule out germ cell tumours.11 12
2 Further imaging
The two most common persistent lesions in premenopausal women are dermoids and endometriomas.13 14 Experienced sonographers can often correctly diagnose complex lesions like dermoid cysts, endometriomas, or haemorrhagic cysts.13 One study found that ultrasound was better than serum CA 125 at discriminating between benign and malignant adnexal masses.15 Many of these common lesions have atypical features, however, and the appearance of benign and malignant cystadenomas overlaps. Early investigators reported that colour Doppler ultrasound could identify malignant ovarian masses (which had low impedance vascular flow, with a pulsatility index of ≤1.0 and a resistance index <0.4), but these results were not reproducible. Other investigators found an overlap in the flow velocity indices of benign and malignant ovarian masses, particularly in premenopausal women.16 17 If sonographic features are inconclusive, magnetic resonance imaging may provide a diagnosis.18
3 Metformin and polycystic ovary syndrome
Most of the initial studies of metformin in the management of polycystic ovary syndrome were observational. A Cochrane review in 2003 suggested that metformin significantly lowered serum androgens, restored menstrual cyclicity, and was effective in achieving ovulation either alone or when combined with clomifene.19 Most of these studies had a small sample size, however, and were underpowered to measure the proposed effects.
In a Dutch trial, 228 women with polycystic ovary syndrome were treated with clomifene citrate plus metformin or clomifene citrate plus placebo. No significant differences were seen in rates of ovulation, continuing pregnancy, or spontaneous miscarriage.20 A significantly larger proportion of women in the metformin group discontinued treatment because of adverse effects. The US Pregnancy in Polycystic Ovary Syndrome (PPCOS) trial enrolled 676 women for six menstrual cycles or 30 weeks, randomised to three treatment arms (metformin 1000 mg twice daily plus placebo, clomifene citrate plus placebo, or metformin plus clomifene citrate).21 Overall, live birth rates were 7%, 23% and 27%, respectively, with rates being significantly lower in the metformin only group than in the other two groups. Miscarriage rates tended to be higher in the metformin only group. Thus, it was concluded that as first line treatment of women with polycystic ovary syndrome who are anovulatory and infertile, metformin alone was significantly less effective than clomifene citrate alone, and that the addition of metformin to clomifene citrate produced no significant benefit.21 Subgroup analysis of women with a body mass index greater than 35 and in those with clomifene resistance did, however, suggest a potential benefit from the combined use of metformin and clomifene citrate.
The patient’s serum testosterone was raised (4.2 nmol/l, upper limit of normal 2.6 nmol/l) but markers of epithelial ovarian cancer (CA 125) and germ cell tumours were negative. Other hormonal investigations (follicle stimulating hormone, luteinising hormone, oestradiol, prolactin, thyroid stimulating hormone) were normal. A repeat ultrasound scan of the pelvis showed a complex mass of the same size with minimal free fluid so magnetic resonance imaging was performed (figs 1 and 2⇓ ⇓). This test showed a mass close to the left ovary, and malignancy could not be ruled out.
Laparoscopy revealed a pedunculated solid and cystic mass of about 5 cm in the left ovary, which was excised in total without breaching the capsule. The left ovary itself looked grossly normal. The patient did not consent to salpingo-oophorectomy. The uterus, both fallopian tubes, and the right ovary were normal. The small amount of peritoneal fluid in the pouch of Douglas was sent for cytology and tested positive for malignant cells. The tumour was reported to be a Sertoli Leydig cell tumour of intermediate to poor differentiation, with no heterologous elements. The patient declined further treatment, and she is still being followed up.
Cite this as: BMJ 2009;339:b3390
Competing interests: None declared.
Provenance and peer review: Not commissioned; externally peer reviewed.
Patient consent obtained.