Women with POI often have complex physical and psychological requirements and therefore a holistic approach to care, often within a multidisciplinary team, is paramount.

 

Sex steroid replacement

Estrogen replacement is important both to manage the symptoms of estrogen deficiency and to minimise the long-term effects on the bones, brain and cardiovascular system. It is recommended that estrogen replacement should be continued up until at least the average age of menopause (51 years). It is important that women are educated regarding the risks and benefits of HRT, in particular that women with POI on HRT have no increased risk of breast cancer before the average age of menopause. HRT is only contraindicated in a very few women with, for example, those with hormone sensitive cancers.

Options for sex steroid replacement include both the combined oral contraceptive (COC) pill or HRT.

  • Hormone replacement therapy

Estrogen replacement, combined with a progestogen in women with a uterus, can be given using many different methods. Oral, patch or gel routes can all be considered and each have their specific pros and cons. Transdermal estrogen replacement has the advantage of avoiding first pass hepatic metabolisms and so is not associated with increased risk of thrombosis.  However, current guidance does not recommend a specific route of choice, as care needs to be individualised.

In contrast to women who have menopause around the average age, women with POI typically need higher estrogen doses (e.g. 2mg orally or 100ug patch) to achieve physiological levels.

Estrogen should be combined with a progestogen in women who have not had a hysterectomy. There are no data in POI to support a specific progestogen. Options include using combined patch or tablet formulations, or combining estrogen (via tablet/patch/gel/implant) with the levonorgestrel-IUS (Mirena®)or micronized progesterone.

There are no specific data to support sequential or continuous combined therapy however, intermittent return of ovarian function may cause breakthrough bleeding on continuous combined HRT regimens.

 

  • COC

Women may prefer to use the COC rather than HRT as it is a simple method of hormone replacement, which may also be seen as more peer-friendly. It also has the advantage that it is currently provided without charge on the NHS, unlike HRT. Due to the potential for intermittent return of ovarian function and ovulation, women with POI still need to consider contraception if they do not want a pregnancy. HRT is not contraceptive (except when using the LNG-IUS as progestogenic opposition) and so the COC may be an appropriate alternative in women who require contraception.

Few studies have compared the long-term effects from estrogen replacement via the COC compared to HRT in women with POI. In a small randomised controlled trial both HRT and the COC were effective for symptom relief and provided bone protection, however HRT appeared to have a more beneficial effect on blood pressure.

NICE Guidelines (2015): Managing premature ovarian insufficiency

  • Offer sex steroid replacement with a choice of HRT or a combined hormonal contraceptive to women with premature ovarian insufficiency, unless contraindicated (for example, in women with hormone-sensitive cancer).
  • Explain to women with premature ovarian insufficiency:
  1. the importance of starting hormonal treatment either with HRT or a combined hormonal contraceptive and continuing treatment until at least the age of natural menopause (unless contraindicated)
  2. that the baseline population risk of diseases such as breast cancer and cardiovascular disease increases with age and is very low in women aged under 40
  3. that HRT may have a beneficial effect on blood pressure when compared with a combined oral contraceptive
  4. that both HRT and combined oral contraceptives offer bone protection
  5. that HRT is not a contraceptive
  • Give women with premature ovarian insufficiency and contraindications to hormonal treatments advice, including on bone and cardiovascular health, and symptom management.
  • Consider referring women with premature ovarian insufficiency to healthcare professionals who have the relevant experience to help them manage all aspects of physical and psychosocial health related to their condition.

Sexual function

Women with POI have been shown to be at higher risk of sexual dysfunction with common problems including reduced arousal, low libido and dyspareunia. Management includes psychosexual counselling, estrogen replacement (both systemic and local if necessary) and consideration given to androgen replacement.

Use of local estrogen can be very beneficial to help prevent and treat vulvovaginal atrophy. Up to 1/3 of women on systemic estrogen will also need local estrogen replacement. Appropriate vaginal lubricants should be advised for intercourse (e.g Yes®, Sylk®). Increasingly complex sexual problems can be seen the younger the age at diagnosis and after certain cancer treatments. Referral to a psychosexual counsellor should be considered for women with POI when sexual problems persist after first line treatments have been tried.

Testosterone replacement is often considered for women with low libido, however there are only limited data regarding the effects of testosterone in POI and no studies have yet looked at sexual function. There are currently no products licensed for use and so testosterone should usually be prescribed following specialist advice.

Currently testosterone replacement is only available in the UK in gel form as the patches were withdrawn for commercial reasons and implants are not presently available.  The gels are designed for use in men and so careful counselling regarding the appropriate dose in women is required. It is normally recommended that women using testosterone have testosterone/free androgen index levels monitored to avoid supra-physiological levels.

Commonly used regimens include:

Testim® gel (10mg testosterone per 1g gel) – one pea sized amount applied to lower abdomen daily – tube to last 10 days

Testogel ® (10mg testosterone per 1g gel) – one pea sized amount applied to lower abdomen daily – tube to last 10 days

Tostran®  (10mg testosterone per 0.5g gel) – one pump (0.5g) every 2 -3 days

 

Lifestyle and dietary advice

In addition to hormone replacement, general lifestyle and dietary advice should be given. This can help manage symptoms of estrogen deficiency and help prevent the long-term effects on the bones and cardiovascular system.

Minimising caffeine and alcohol, not smoking and regular weight bearing exercise will all be beneficial. A daily dietary intake or supplementation of calcium (1000 mg) and Vitamin D (800 IU) is recommended. There is currently no evidence to support routine calcium or vitamin D replacement unless deficient, however there may be benefit for supplementation in women with low bone density.

 

Alternative therapies

 

Hormone replacement will be contraindicated in a few women and other women may choose not to use HRT. Non-hormonal treatments such as SNRIs (venlafaxine), SSRIs and gabapentin have some evidence of benefit for vasomotor symptoms in the wider menopause population but there are no data specific to POI. Furthermore these agents will not protect against cardiovascular disease and osteoporosis.  There are no studies using complementary or herbal medicinal products in the POI population.

 

 

 

References

  • Panay N, Hamoda H, Arya R, Savvas M; British Menopause Society and Women’s Health Concern. The 2013 British Menopause Society & Women’s Health Concern recommendations on hormone replacement therapy. Menopause Int. 19, 59–68 (2013).
  • Langrish JP, Mills NL, Bath LE et al. Cardiovascular effects of physiological and standard sex steroid replacement regimens in premature ovarian failure. Hypertension 53, 805–811 (2009).
  • Crofton PM, Evans N, Bath LE et al. Physiological versus standard sex steroid replacement in young women with premature ovarian failure: effects on bone mass acquisition and turnover. Clin. Endocrinol. (Oxf.) 73, 707–714 (2010).
  • http://www.nice.org.uk/guidance/ng23/chapter/Recommendations#diagnosing-and-managing-premature-ovarian-insufficiency
  • De Almeida DM, Benetti-Pinto CL, Makuch MY. Sexual function of women with premature ovarian failure. Menopause 18, 262–266 (2011).
  • Wierman et al. Androgen Therapy in Women: A Reappraisal: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 99(10):3489–3510 (2014)