The effect of obesity on menarche and the menopause

Several epidemiological studies have suggested that changes in body weight and composition are crucial in regulating pubertal development in women . The relationship between obesity and reproductive disturbances, and most likely menstruation, appears to be stronger for early-onset obesity . Leptin is a main product of body fat and regulates the gonadotrophin surge, which initiates the development of pubertal stages . Several studies have reported that the age of menarche generally occurs at a younger age in obese girls than in normal-weight girls .

Furthermore, data also suggest that the onset of ovarian failure and increased production of follicle-stimulating hormone (FSH) at menopause occurs several years earlier in obese than in normal-weight women .

Hormonal effects

Obesity is associated with elevated levels of oestrogen through peripheral conversion of androgens to oestrogen, in particular, androstenedione, in adipose tissue by aromatase . Obese women also have decreased SHBG levels , which cause increased levels of circulating or free testosterone. In addition, elevated insulin levels stimulate the production of androgens in ovarian stromal tissue. These changes in the concentration of gonadal steroid hormones with obesity cause disruption of normal ovulation and menstrual disorders including irregular menstrual bleeding, oligomenorrhoea and amenorrhoea and are often associated with heavy dysfunctional uterine bleeding.

A study of obese girls with oligomenorrhoea reported that there was an increased luteinising hormone pulse frequency , whereas women who regularly menstruate have a lower FSH to LH ratio . However, in uncomplicated obesity, with regular menstrual cycles and normal progesterone levels, lower levels of oestradiol and inhibin B are found . A later study by the same group also identified that women with oligomenorrhoea had a higher central fat accumulation, BMI, insulin levels and insulin resistance, compared to women with normal menstrual cycles; furthermore, oligomenorrhoea was independently associated with waist circumference .

Obesity, endometrial hyperplasia and cancer

Polycystic ovary syndrome (PCOS) is associated with endometrial cancer due to chronic anovulation, with prolonged endometrial exposure to unopposed oestrogen in the absence of sufficient progesterone , which is significantly associated with the risk of developing endometrial hyperplasia . A meta-analysis comprising 4056 women estimated that the odds of developing endometrial cancer was almost three times higher (odds ratio (OR) 2.70, 95% confidence interval (CI) 1.00–7.29) in women with PCOS compared to controls . These data translate into a 9% lifetime risk of developing endometrial cancer in PCOS versus 3% in the general population. Supporting this, a population-based, case–control study of endometrial cancer and PCOS has reported that this increased endometrial cancer risk related to PCOS is reduced by almost one-half when adjusted for BMI (OR 2.2, 95% CI 0.9–5.7), emphasising obesity as a confounding risk factor for developing endometrial cancer .

Challenges in the management of obese women with HMB

Obesity is associated with numerous co-morbidities, such as hypertension, diabetes, ischaemic heart disease and increased risk of venous thromboembolism (VTE), all of which need to be considered when planning investigations and treatment of menstrual disorders. Thus, the decision-making process on modalities of treatment is based on a balance between expectant benefits and the potential risks (benefits/risk ratio). The following aims to outline the challenges in investigating obese women and discuss the efficacy of treatment modalities so benefits can be ascertained, along with the likely risks, in order to give an overview of management options. Technical issues have also been discussed where appropriate ( Table 1 ).

The treatment of oligomenorrhoea, amenorrhoea and associated anovulation in obese women has been widely reported, while treatment modalities for heavy menstrual loss in this population still needs further high-quality evidence. To date, the effectiveness of treatment options offered to obese women presenting with HMB is often based on indirect evidence or evidence from trials carried out on general and/or normal-weight women. Here, a focus on the management of HMB integrating the current and limited evidence of effect and their potential associated risks and challenges is attempted.

Investigations of HMB in obese women

As the risk of endometrial hyperplasia is increased in overweight women, a lower threshold for carrying out endometrial sampling should be used. The National Institute for Health and Care Excellence (NICE) guidance suggests that women who are ≥45 years of age have persistent intermenstrual bleeding, or are unresponsive to treatment, should have an endometrial sample taken .

Hysteroscopy may be required in some women, for example, those with any ‘red flag’ symptoms such as intermenstrual bleeding, post-coital bleeding or a sudden change in their bleeding pattern. To avoid the need for anaesthesia and its associated risks, this can frequently be carried out in the outpatient setting. However, in the morbidly obese woman, attention needs to be paid to the equipment used, as examination couches tend to have an upper weight limit and positioning of the patient may be difficult. Carrying out the procedure via vaginoscopy removes the need for large speculae, but any operative procedure, such as polypectomy, can be technically challenging due to the length of the scope and instruments.

Conservative measures for HMB and the role of weight control in the management of HMB

Given the effects of obesity on the menstrual cycle and reproductive function, patients should be encouraged to maintain a normal weight and obese patients should be counselled that weight loss may ameliorate their menstrual dysfunction. Obese women with insulin resistance may also benefit from metformin therapy, although at present this is not routinely used, especially without a previous diagnosis of PCOS.

In women who are oligomenorrhoeic (or anovulatory), weight loss can restore cyclicity. It was reported that, among 98 obese women who were anovulatory preoperatively, 70 women (71.4%) regained normal menstrual cycles following bariatric surgery .

It has been suggested that weight loss restores regular menstrual function by decreasing the aromatisation of androgens to oestrogens in adipose tissue. In a randomised, double-blind, placebo-controlled study of 143 obese oligo- or amenorrhoeic women with PCOS randomised to receive metformin or placebo, weight loss alone correlated with an improvement in menses . Weight loss also improves menstrual function by increasing insulin sensitivity. Obese women also have a degree of insulin resistance, a characteristic feature of PCOS. A number of studies support the ability of metformin to restore normal menses in women with HMB .

Use of tranexamic acid during menstruation is a simple first-line measure that can help to reduce blood flow. Menstrual blood loss can be reduced by up to 60% by taking tranexamic acid . Tranexamic acid is an anti-fibrinolytic agent that reduces menstrual blood loss by inhibiting the action of plasmin, the enzyme that breaks down fibrin. Due to its effect on clotting, there is a potential increased risk of VTE. Obesity, alongside other significant risk factors for VTE, contraindicates the use of tranexamic acid. For this reason, it should be avoided in women already taking the COCP in order to avoid the cumulative thrombogenic effect of these two agents.

Non-steroidal anti-inflammatory drugs (NSAIDs) can be used alongside tranexamic acid and will reduce symptoms of dysmenorrhoea . This treatment has the benefit of avoiding the risks of hormonal preparations.

Hormonal treatments for HMB

The effectiveness of treatment strategies, particularly hormonal ones, tends to be stipulated from their effectiveness in the suppression of ovulation and achievement of effective serum levels but not necessarily from control of heavy menstrual loss or patient acceptability.

Hormonal preparations are the mainstay of non-surgical treatments in women with HMB. Some will also offer the benefit of cycle regularity in those with irregular bleeding or oligomenorrhoea. These treatment options include combined oral contraceptive pills (COCP), progestogen-only pill (POP), subdermal progestogen implants and progestogen-releasing intrauterine devices. Doubt as to the efficacy of some of the treatments in women with a high BMI have been raised by some previous studies , suggesting that body habitus may affect the metabolism of hormonal preparations such as the COCP and that failure in terms of pregnancy rates may be more likely in overweight women.

In attempting to determine the effectiveness of hormonal modalities, in terms of treating heavy menstrual loss, difficulties are encountered as the effectiveness (or lack) of these hormonal preparations is often reported with respect to their contraceptive efficacy. One would stipulate that the effect of the hormonal treatment on menstrual blood loss is likely to be reduced, should the contraceptive efficacy or serum hormone levels be affected by weight.

Combined oral contraceptive pill

Traditionally the COCP has been used extensively to treat HMB, whilst providing the additional benefit of effective contraception and cycle control.

In women with PCOS, additional benefits of the combined pill are due to their action, as levels of SHBG are increased and free testosterone are reduced by the COCP. This signifies that ‘the pill’ can be beneficial as a treatment of the acne and hirsutism associated with PCOS. In addition, the effect of the progestogen on the endometrium, opposing the chronic high level of oestrogen exposure and the restoration of a regular (withdrawal) bleed, reduces the risk of endometrial hyperplasia and subsequent endometrial cancer. The Royal College of Obstetricians and Gynaecologists (RCOG) advises that women with oligo- or amenorrhoea and PCOS be treated with progestogens to induce a withdrawal bleed three to four times a year .

Obesity alone should not rule out the use of the COCP. Both the World Health Organization (WHO) and UK Medical Eligibility Criteria for contraception support the use of the COCP when potential benefits outweigh the risks (category 2) for women with a BMI between 30 and 34 kg/m . In women with a BMI >35, the category changes to 3 indicating that the risks may outweigh possible benefits. Avoidance of the COCP in women with a previous or current history of VTE, thrombogenic mutations, hypertension and cardiovascular disease, migraine with aura and breast cancer still applies. Obesity is often associated with other risk factors, including those listed above, thus increasing the cumulative risk, which will outweigh the likely benefits, and in these circumstances an alternative should be considered.

Studies into the efficacy of the COCP report ovulation suppression and contraception as a primary outcome of effectiveness. The effect on menstrual cycle is often reported as a secondary outcome in terms of regularity of the withdrawal bleed but not in terms of reduction of menstrual blood loss.

Some studies have shown mixed results in terms of effectiveness of the COCP in overweight women. It is suggested that contraceptive failures were more common in overweight or obese women . However, a published review revealed flaws in the data collection, in view of BMI being self-reported, adherence to the COCP not being reviewed, or examined retrospectively, and a lack of adjustment for parity . The review concluded that there was no convincing evidence to suggest the COCP is less effective in women with a raised BMI as opposed to women of normal weight.

In response to the mixed data on COCP efficacy amongst women with different BMI, data were analysed from the results of the pharmacokinetics of COCP in normal and overweight women . This showed lower peak circulating levels of ethinyl estradiol and levonorgestrel in the overweight group, with a more significant difference in the levels of ethinyl estradiol. The trough levels of both drugs were, however, similar, regardless of BMI. Ovarian follicular activity was investigated sonographically along with serum levels of exogenous hormones. Consequently, the mean endometrial thickness was measured and recorded during the study cycle, and was similar for obese and normal-weight participants (6.9 vs. 6.3 mm, respectively, p = 0.68). One could then postulate that the effect on the endometrium, and therefore the treatment of HMB, should be similar amongst normal-weight and overweight women.

As a response to these results, a European study looked at >110,000 women in several countries to determine the effect of age, weight, BMI and other factors on the efficacy of the COCP . No significant discrepancy could be found amongst women using the COCP containing most types of progestogens and, regardless of BMI, pregnancy rates with the use of the COCP remain low.

Furthermore, a recent Cochrane review concluded that BMI did not affect the efficacy of the COCP. Therefore, when considering treatment options for obese women, the use of the COCP remains a viable option in those with a BMI of up to 35, bearing in mind the frequently occurring co-morbidities, which increase the risks associated with this modality of treatment.

Progestagen-releasing intrauterine devices

Guidance from the National Institute for Clinical Excellence (NICE) suggests that the levonorgestrel-releasing intrauterine system (LNG-IUS) (Mirena) should be used as the first-line treatment for HMB . The Mirena works by slowly releasing a low dose of levonorgestrel, which acts locally on the endometrium, preventing proliferation and thus thinning the lining of the womb. The amount of blood lost during menstruation therefore subsequently reduces.

The Mirena IUS is graded as category 1 on the UK Medical Eligibility Criteria for women who are obese, although in women with multiple risk factors, the Mirena IUS is given a category 2 . Category 2 is defined as a condition where the advantages of using the method generally outweigh the theoretical or proven risks; however, in many obese women avoiding the need for surgery will be of greater benefit than any of the possible risks. The Mirena IUS falls into category 2 when cardiovascular risk factors are present due to the theoretical effect of levonorgestrel on lipid metabolism and has been extrapolated from other studies that some progestogens may increase the risk of thrombosis.

In the past, intrauterine devices were often offered to older, multiparous women; however, increasingly they seem more acceptable to all women, even adolescents. An American study of 25 teenagers undergoing bariatric surgery interviewed the teenagers regarding menstrual disorders, educated them in the benefits of the LNG-IUS and then offered the LNG-IUS to be fitted at the time of surgery to provide effective post-operative contraception and treatment of menstrual disorders. Of the 25 adolescents, 23 were happy to have the LNG-IUS fitted; this demonstrates the high rate of acceptability in this method by teenagers when well informed and where dysfunctional bleeding is common .

The majority of women fitted with a Mirena IUS experience a significant reduction in the amount of menstrual blood loss. Comparative studies suggest that the majority of women will have a reduction in menstrual blood loss in the first 6 months from insertion, and 88–94% will have noticed a significant improvement in their bleeding by 12 months . These studies did not examine effectiveness in overweight women; however, a European cross-sectional study looked at patient satisfaction with the IUS in overweight and obese women . The rates of satisfaction increased with decreasing menstrual blood loss and by achieving amenorrhoea. They found that women with a lower BMI were more likely to be ‘very’ or ‘quite satisfied’ with the IUS, and more often achieve amenorrhoea than women with a BMI >25. However, women with a raised BMI were more likely to have heavier menstrual bleeding and take longer to achieve amenorrhoea, typically 6–12 months after insertion, but the number of women achieving amenorrhoea continued to increase with duration of use.

There may be technical difficulties of inserting the intrauterine contraceptive device (IUCD) in women with an increased BMI, including the inability to determine the size and position of the uterus by bimanual examination, and difficulty in visualising the cervix. Placing the patient in the lithotomy position and using a long speculum may provide better exposure. An ultrasound scan may need to be used as an adjunct to determine the uterine position and direction; there may be a role for fitting the device under ultrasound scan guidance.

Although the evidence is scanty and indirect in that it uses patient satisfaction as a marker for improved bleeding, it may be concluded that there is less patient satisfaction and more treatment failure in obese women when using the Mirena IUS. However, it is of low risk, with minimal side effects and can be inserted in the outpatient setting. Clinicians should continue to offer this treatment to obese women who wish to choose this modality.

Surgical treatments for HMB

Many women with HMB are not satisfied with medical treatment, resulting in the need for surgery. Endometrial ablation and hysterectomy are the main surgical approaches to the treatment of HMB. Recommendations by NICE are that these modalities should only be considered if quality of life is severely affected or medical therapies are not tolerated or ineffective . Desire for future fertility needs to be taken into consideration, as both ablation and hysterectomy are incompatible with future pregnancy.

Traditionally, hysterectomy was regarded as the definitive surgical treatment for HMB with a 100% success rate in amenorrhoea and high levels of satisfaction; however, it is a major surgical procedure with significant physical complications and a long recovery time. With this in mind, many women prefer a less invasive treatment, even though the success rate is lower . Furthermore, within an obese population, these strategies may be associated with further complications.