Femoston vs tibolone hormone replacement therapy 1.5.15

Editor's Notes

1. Clinical examination includes a holistic approach to health, rather than simply looking for features of menopause in isolation and this leads to diagnose the latent and overt non communicable disease. Examination can be broadly divided into three main categories: I. General physical examination: Examination of respiratory, cardiovascular system, and bones may detect common age related problems II. Breast examination: This should be carried out regularly due to an increased risk of breast cancer as women get older III. Pelvic examination: This is performed to assess for complications of menopause, such as urogenital atrophy and must include PAP smear. Ref.: Meeta, et al.: Guidelines on menopause. Journal of Mid-life Health ¦ Apr-Jun 2013 ¦ Vol 4 ¦ Issue 2 Counseling: To address women’s questions and concerns, providing patient education, and enhancing the patient’s confidence in the decision making. Diet and Exercise prescription: Physical exercise helps to maintain a healthy weight, improves bone density, coordination and balance, genitourinary problems, relieves depression, and induces sleep. Social interactions either in an exercise program or otherwise, help the post‑menopausal women to improve mood, relieve depression, and anxieties. Pharmacotherapy: Low quality and grade C evidence: Phytoestrogens and lycopene rich foods in the Indian diet Hormone therapy: Estrogens, progestogens, combined therapies, and tibolone. 3 indications for post‑menopausal HT, which have constantly withstood the test of time, derived from the results of various clinical trials are the beneficial effect of estrogens on symptom relief, urogenital atrophy, and bone. Ref.: Meeta, et al.: Guidelines on menopause. Journal of Mid-life Health ¦ Apr-Jun 2013 ¦ Vol 4 ¦ Issue 2
2. Estrogens are synthesised by the ovary and placenta. As for other steroids, the starting substance for estrogen synthesis is cholesterol. There are three main endogenous estrogens in humans: estradiol, estrone and estriol . Estradiol is the most potent form of estrogen. It is the primary type of estrogen produced by the ovaries during a woman’s reproductive years.  As these hormones pass through the liver, it is the liver’s job to detoxify and metabolize estradiol and estrone to a weaker form known as estriol. This weakest form of estrogen is 80 times weaker than estradiol. Estrone is an intermediate-potency form of estrogen, 12 times weaker than estradiol. It is mainly produced within the fatty tissue of the body from precursor hormones made by the adrenal glands. Obviously, the more weight a woman carries, the more adrenal estrogen she is capable of making. The ovaries also produce small amounts of estrone after menopause, when production of estradiol ceases. As these hormones pass through the liver, it is the liver’s job to detoxify and metabolize estradiol and estrone to a weaker form known as estriol. This weakest form of estrogen is 80 times weaker than estradiol. Ref.: Rang & Dale’s Pharmacology, 6th edition. DRUGS AFFECTING MAJOR ORGAN SYSTEMS > 30 The reproductive system
3. Several types of estrogen are used in HRT, at varying doses. Different doses may be appropriate for different women at different menopausal stages. ‘Medium’ doses of estrogen are generally effective against the onset of vasomotor and psychological symptoms. For many women, low-doses of estrogen provide adequate relief of symptoms with high rates of amenorrhea, and so higher doses are not required. ‘Low’-dose HRT schedules are effective in controlling subjective symptoms in postmenopausal women and still increase bone density in postmenopausal women. Reference: Gambacciani M, Genazzani AR. Maturitas 2001;4:195–201.
4. The necessity of adding a progestogen to HRT for women who have not had a hysterectomy was demonstrated in this 3-year, multicenter, randomized, double-blind, placebo-controlled trial. The effects of progestogen on the endometrium were examined in 596 postmenopausal women aged 45–64 years who received: Placebo, Conjugated equine estrogens (CEE) 0.625 mg/day alone, CEE 0.625 mg/day plus sequential medroxyprogesterone acetate (MPA) 10 mg/day for the first 12 days, CEE 0.625 mg/day plus continuous MPA 2.5 mg/day, or CEE 0.625 mg/day plus micronized progesterone 200 mg/day for the first 12 days. In women given CEE alone, 62% developed some type of endometrial hyperplasia and 34% had complex hyperplasia or atypia. Incidence of abnormal biopsy specimens was low for women receiving combination regimens, with no significant difference between placebo and any of the three combined regimens (p=0.16). The authors concluded that postmenopausal women with a uterus who receive estrogen replacement therapy should use regimens with additional progestogen for endometrial protection. Reference: Writing Group for the PEPI Trial. JAMA 1996;275:370–5.
5. This slide summarizes the receptor-binding profiles of the different progestogens. Besides the progestogenic effect, which is in common for all progestogens, there is a wide range of biological effects, which are different for the various compounds.1 Dydrogesterone appears to be a highly selective progestogen which binds almost exclusively to the progesterone receptor. Due to its selectivity, effects not mediated by the progesterone receptor are minimal or absent.1 In contrast, other progestogens have effects via estrogenic, androgenic, or glucocorticoid.1,2 References: 1. Schindler AE. Maturitas 2003;46(S1):7–16. 2. De Gooyer ME et al. Steroids 2003;68:21–30.
6. The IMS states that MHT remains the most effective therapy for vasomotor symptoms and urogenital atrophy. They should be treated with the lowest effective dose. MHT must be individualized and tailored according to symptoms and the need for prevention. Women can have the option of HRT for as long as they derive symptomatic benefit and are aware of the risks for their regimen and personal circumstances. The risk/benefit balance needs to be evaluated as the risks and benefits differ for women during the menopause transition compared with those for older women. The importance of the age at initiation and the good safety profile of HRT in women younger than 60 years was demonstrated by the Women’s Health Initiative (WHI) study. Whether or not to continue therapy should be decided at the discretion of the woman and her physician depending on the goals and estimation of ongoing benefits and risks. Micronized progesterone or dydrogesterone used in association with oral or percutaneous E may be associated with a better risk profile for breast cancer than other synthetic progestogens . In menopausal women younger than 45 years, HRT may reduce symptoms and preserve bone density and is advised at least until the average age of menopause. Reference: De Villiers TJ et al. Climacteric 2013;16:316–337.
7. The IMS states that MHT remains the most effective therapy for vasomotor symptoms and urogenital atrophy. They should be treated with the lowest effective dose. MHT must be individualized and tailored according to symptoms and the need for prevention. Women can have the option of HRT for as long as they derive symptomatic benefit and are aware of the risks for their regimen and personal circumstances. The risk/benefit balance needs to be evaluated as the risks and benefits differ for women during the menopause transition compared with those for older women. The importance of the age at initiation and the good safety profile of HRT in women younger than 60 years was demonstrated by the Women’s Health Initiative (WHI) study. Whether or not to continue therapy should be decided at the discretion of the woman and her physician depending on the goals and estimation of ongoing benefits and risks. Micronized progesterone or dydrogesterone used in association with oral or percutaneous E may be associated with a better risk profile for breast cancer than other synthetic progestogens . In menopausal women younger than 45 years, HRT may reduce symptoms and preserve bone density and is advised at least until the average age of menopause. Reference: De Villiers TJ et al. Climacteric 2013;16:316–337.
8. Pre‑HT work‑up and an annual follow‑up are essential when prescribing HT. The dose and duration of use of HT should be individualized and a risk–benefit assessment carried out annually. A full gynecological assessment is mandatory prior to starting HT and at regular intervals thereafter. Self‑breast examination is advised monthly and CBE at least annually. Mammogram/US, where available should be carried out 1‑3 yearly if the initial mammogram is normal (Grade C). Ref.: Meeta, et al.: Guidelines on menopause. Journal of Mid-life Health ¦ Apr-Jun 2013 ¦ Vol 4 ¦ Issue 2 Guidelines issued by the European Menopause and Andropause Society recommend: Initial follow-up about 3 months after starting a new HRT regimen. This is because most symptoms will have responded by this time and any persistent side effects will be apparent. The effectiveness of treatment against menopausal symptoms and whether there are any adverse effects should be determined and the regimen adjusted as necessary. Follow-up thereafter: Regular checkups (at least once a year) to discuss benefits and risks More frequent follow up in women with concomitant medical conditions, such as CVD, diabetes, epilepsy.
9. There are no reasons to place arbitrary limitations on the duration of MHT. Data from the WHI trial and other studies generally support safe use for at least 5 years in healthy women initiating treatment before age 60 or within 10 years after menopause. Continued use beyond the 5-year window may be appropriate, based on a woman’ s individual risk profile. Women taking MHT should have at least an annual consultation to include a physical examination, update of medical and family history, relevant laboratory and imaging investigations, a discussion on lifestyle, and strategies to prevent or reduce chronic disease. Duration of use: Premature menopause‑HT: Can be prescribed up to the natural age of menopause; further continuation of therapy is a shared decision between the woman and the physician according to the indication and the need Natural menopause: Safety data of EPT therapy with CEE+MPA is 3‑5 years. Role of extended use of HT is a shared decision between the woman and the physician and may be considered in cases of recurrence of symptoms after stopping therapy, in cases of management of osteoporosis when other therapies are contraindicated (Grade A). Ref.: Meeta, et al.: Guidelines on menopause. Journal of Mid-life Health ¦ Apr-Jun 2013 ¦ Vol 4 ¦ Issue 2 MHT has the potential for improving the cardiovascular risk profile through its beneficial effects on vascular function, cholesterol levels and glucose metabolism. MHT also reduces the risk of diabetes and, through improving insulin action in women with insulin resistance, it has positive effects on other related risk factors for cardiovascular disease such as the lipid profile and metabolic syndrome. The degree of association between breast cancer and postmenopausal MHT remains controversial. The possible increased risk of breast cancer associated with MHT is small (less than 0.1% per annum, or an incidence of 1.0 per 1000 women per year of use), and lower than the increased risks associated with common lifestyle factors such as reduced physical activity, obesity and alcohol consumption. Randomized controlled data from the WHI study demonstrated no increased risk in first-time users of MHT during the 5 – 7 years since initiation of treatment. References: De Villiers TJ et al. Climacteric 2013;16:316–337.Santen RJ et al. J Clin Endocrinol Metab 2010;95(Suppl 1):S1–S66. A large European observational study suggested that: Dydrogesterone used in association with oral or percutaneous estradiol may be associated with a better risk profile for breast cancer than synthetic progestogens Registry study from Finland: No increase in risk with dydrogesterone after at least 5 years of use compared to synthetic progestogens which were associated with a small increase in risk de Villiers et al. CLIMACTERIC 2013;16:316–337. 2013 International Menopause Society The WHI estrogen plus progestin study (n=16,608 women with an intact uterus) demonstrated a relative risk for breast cancer of 1.24 (95% CI 1.00 –1.59) with current use of MHT (CEE/MPA) vs. placebo.1 This translates to an excess (attributable) risk of 4 women with breast cancer per 1000 women taking HRT for 5 years.2 However, later studies with adjusted confidence intervals have indicated that the results of WHI were not significant.3 Excess risk of breast cancer from MHT increases with increase in underlying risk such as determination of risk (genetic alterations and inherited mutations) should underlie decision to use HRT.5 Therefore, determination of risk should underlie the decision to use HRT. References: Rossouw JE et al. JAMA 2002;288:321–33. Santen R et al. J Clin Endocrinol Metab 2010;95(Suppl 1):s1–66. Langer R et al. Climacteric 2012;15:206–12. Stefanik M et al. JAMA 2006;295:1647–57. Gompel A et al. Climacteric 2012;15:241–9.
10. The 2013 International Menopause Society recommendations on MHT and preventative strategies for midlife health states that: MHT is effective in preventing the acceleration of bone turnover and the bone loss associated with the menopause MHT decreases the incidence of all osteoporosis-related fractures, including vertebral and hip fractures, even in women not at high risk of fracture In postmenopausal women at risk of fracture and younger than 60 years, or within 10 years of menopause, MHT can be considered as one of the first-line therapies for the prevention and treatment of osteoporosis-related fractures. The recommendations highlight the global consensus that MHT is an effective treatment for the prevention of fracture in at-risk women before age 60 years or within 10 years after menopause. The initiation of hormonal therapy for the sole purpose of the prevention of fractures after the age of 60 years is currently not recommended since the risk of long-term complications, e.g. breast cancer, outweighs the potential benefits. Reference: De Villiers TJ et al. Climacteric 2013; 16:316–37.
11. E3N is a prospective cohort comprising 98,995 women born between 1925 and 1950. In the French E3N cohort study, 2,354 cases of invasive breast cancer occurred among 80,377 postmenopausal women during 8.1 years of follow-up.1 The risk for all breast cancers associated with combined HRT varied according to progestogen type .1 1.00 for E/progesterone 1.16 for E/D 1.69 for E/other progestogens The authors concluded that the findings suggest that choice of progestogen component for MHT may be an important factor regarding breast cancer risk. Fournier A et al. Breast Cancer Res Treat 2008;107:103–11. Fournier A et al. J Clin Oncol. 2008 ;26:1260–1268.
12. Follow-up started either at the date the 1992 questionnaire was returned for already postmenopausal women, or at the date menopause was first reported. Follow-up ended at the date of diagnosis of any cancer, the date of the last completed questionnaire, or June 2008 78,353 women Hazard ratio can be interpreted as the chance of an event occurring in the treatment arm divided by the chance of the event occurring in the control arm, or vice versa, of a study. Hazard ratios differ from relative risks in that the latter are cumulative over an entire study, using a defined endpoint, while the former represent instantaneous risk over the study time period, or some subset thereof. Hazard ratios suffer somewhat less from selection bias with respect to the endpoints chosen and can indicate risks that happen before the endpoint. Other Progestagens: Chlormadinone acetate, cyproterone acetate, demegestone, dienogest, drospirenone, ethynodiol acetate, gestodene, levonorgestrel, lynestrenol, medrogestone, medroxyprogesterone acetate, megestrol acetate, nomegestrol acetate, norethisterone acetate, and promegestone.
13. ESTHER was a multicenter case-control study looking at the impact of route of estrogen administration and progestogen on the risk of venous thromboembolism (VTE) among postmenopausal women (aged 45–70 years) receiving HRT. The study included 271 consecutive cases with a first documented episode of idiopathic VTE and 610 controls matched for center, age, and admission date. Overall, users of oral estrogen had an approximately 4-fold increased risk of VTE compared with non-users. This increased risk was not seen with transdermal estrogen (adjusted OR 0.9, 95% CI 0.4 to 2.1). There was no significant association of VTE with micronized progesterone or pregnane derivatives (which included dydrogesterone, medrogestone, chlormadinone acetate, cyproterone acetate, and MPA). Norpregnane derivatives (either nomegestrol acetate or promegestone) were also associated with an approximately 4-fold increased risk of VTE vs. no use. The results suggest that norpregnane derivatives may be thrombogenic, whereas micronized progesterone and pregnane derivatives appear to have an acceptable thrombotic risk profile. Reference: Canonico M. Circulation 2007;115:840–5.
14. To compare the effects of 17-oestradiol plus dydrogesterone with conjugated equine oestrogens plus medroxyprogesterone acetate on serum lipids, apolipoproteins and lipoprotein(a) in postmenopausal women. Methods: A multi-centre, prospective, randomized, double-blind, comparative one-year study in 362 healthy postmenopausal women aged 39–74 years with an intact uterus. Fasting blood samples were taken at baseline and after 28 and 52 weeks of treatment. Participants received daily oral treatment: Continuous combined 1mg micronized 17-oestradiol/5 mg dydrogesterone (E/D: n= 180) or 0.625 mg conjugated equine oestrogens/5 mg medroxyprogesterone acetate (CEE/MPA: n= 182) Results: Significant differences between the two groups after 52 weeks: HDL-cholesterol (E/D: +15.3%; CEE/MPA: +7.5%) VLDL-triglycerides (E/D: −3.3%; CEE/MPA: +10.0%) Total cholesterol (E/D: −1.7%; CEE/MPA: −7.3%) LDL-cholesterol (E/D: −4.5%; CEE/MPA: −11.3%) Triglycerides (E/D: +9.8%; CEE/MPA: +16.6%)
15. The effect of E/D on lipid profile was compared with that of CEE/norgstrel Prospective, randomized, double-blind, multi-centre study involving 193 peri- and post-menopausal women. Participants received six 28-day cycles of oral sequential E1 mg/D 10 mg or CEE 0.625 mg/norgestrel 0.15 mg for 24 weeks. Results: There was a significant increase in HDL cholesterol at both 12 and 24 weeks in the E/D group vs. baseline, whereas there was a significant decrease from baseline at both time points in the CEE/norgestrel group LDL cholesterol levels decreased significantly in both treatment groups, both at week 12 and at week 24 No significant effect on triglycerides was observed Results suggest that sequential E/D may have a more beneficial effect on lipid profiles compared with CEE/norgestrel. Reference: Cieraad D et al. Arch Gynecol Obstet 2006;274:74–80.
16. Sequential E/D has also been shown to be associated with favourable changes in serum lipid profile. In this double-blind, placebo-controlled study, 579 postmenopausal women were randomized to oral treatment with placebo, sequential E 1 mg/D 5 or 10 mg, or sequential E 2 mg/D 10 or 20 mg for 26 cycles. After 13 cycles, the increase in HDL cholesterol seen in the 1/10 mg, 2/10 mg and 2/20 mg groups was significantly higher than in the placebo group (p<0.01). The largest increase was seen in the 2/10 mg group. A further increase in HDL cholesterol levels was observed after 26 cycles, with all four active treatment groups causing a significantly greater increase than placebo (p<0.05). In addition, LDL cholesterol and lipoprotein(a) levels were significantly reduced, (with the exception of 1/10 treatment group that did not see significant reduction in LDL at 26 weeks) and apolipoprotein A1 levels were significantly increased, in all active treatment groups after 13 and 26 cycles. Reference: Stevenson J et al. Climacteric 2005;8:352–9.
17. Menopause decreases insulin secretion and elimination, with an associated increased risk of diabetes. This prospective randomized, double blind, 2 year trial investigated whether E/D could affect these changes in 32 post-menopausal women aged 40-65. Postmenopausal women were randomized to sequential E 1 mg/D 5 or 10 mg (‘low dose’; n=15) or E 2 mg/D 10 or 20 mg (‘high dose’; n=9). In both the low- and high-dose E groups there were significant reductions in fasting glucose and fasting insulin from baseline (data shown for low-dose group only). Pancreatic insulin secretion during an intravenous glucose tolerance test was also significantly increased from baseline with treatment, as was insulin elimination at both the peripheral and hepatic levels. These results highlight that E/D can affect menopause-associated changes in insulin secretion and elimination. Low-dose 1/5 sequential is not commercially available. Reference: Godsland IF et al. Clin Endocrinol (Oxf) 2004;60:541–9.
18. The effects of sequential E/D on blood pressure (BP) were evaluated in this randomized study of 29 healthy normotensive postmenopausal women, with a mean age of 52 years and median duration of amenorrhea of 35 months. Participants sequential E 1 mg/D 5 or 10 mg (n=14) or no therapy (n=15) for 12 months. The women underwent 24-hour ambulatory BP monitoring at baseline and at 3 and 12 months of follow-up. Ambulatory systolic BP increased significantly in the control group at 3 months of follow-up and showed a consistent and significant decline in the HRT group at 12 months. Diastolic BP also declined significantly from baseline in the HRT group and increased in the control group. Office BP measurements did not differ between the two groups. The results suggest that E/D may have BP-lowering properties in healthy, normotensive postmenopausal women. Reference: Van Ittersum FJ et al. Am J Hypertens 1998;11:1147–52.
19. Change in body weight or BMI Women perceive that initiation of MHT causes “weightgain.” However, the majority of studies (but not all) suggest the opposite, that MHTusers gain less weight or body fat than do non-users. The effect of treatment for 2 years with Femoston estradiol 2 mg/dydrogesterone 10 mg, compared with a transdermal MHT formulation, tibolone, or no treatment, on body composition and weight was assessed in a study involving 100 postmenopausal women. After 2 years, total body fat mass increased by 3.6% in women not taking HRT and by 4.7% in those using transdermal HRT (both p<0.05 vs. baseline), while there was no significant change in tibolone users. However, body fat mass was reduced (–1.2%) in those using Femoston.
20. According to treatment guidelines, HRT must be individualized and tailored according to symptoms and the need for prevention. A number of studies have evaluated the effects of Femoston® vs. other HRTs and shown that, when used by the right woman, at the right dose, Femoston® can: Relieve vasomotor and other menopausal symptoms Provide protection against bone loss as a second-line therapy Provide acceptable bleeding patterns.
21. Cochrane Database of Systematic Reviews 2012: Tibolone is a synthetic prohormone with weak estrogenic, progestinic, and androgenic actions. Tibolone, used at the daily dose of 2.5 mg, may be less effective than combined HT in alleviating menopausal symptoms although it reduced the incidence of vaginal bleeding. There was evidence that treatment with combined HT was more effective in managing menopausal symptoms than was tibolone. Available data on the long term safety of tibolone is concerning given the increase in the risk of breast cancer in women who had already suffered from breast cancer in the past and in a separate trial the increase in the risk of stroke in women whose mean age was over 60 years. Similar concerns may exist for estroprogestins but their overall benefit-risk profile is better known and is more directly related to women with menopausal symptoms. CEE - Conjugated equine estrogens 0.625 mg continuously combined with medroxyprogesterone acetate 5 mg (CEE-MPA)/day administered for 12 month. Total number of events including vaginal dryness and painful sexual intercourse are less with combined HT as compared with tibolone in three clinical trials. CEE - Conjugated equine estrogens 0.625 mg continuously combined with medroxyprogesterone acetate 5 mg (CEE-MPA)/day administered for 12 month
22. Hänggi et al. 1997. British Journal of Obstetrics and Gynaecology. 1997;104:708–17 Untreated, n=35 Oral E 2 mg/D10 mg, n=35 Transdermal E 50 mcg/D 10 mg, n=35 Tibolone 2.5 mg, n=35 Duration – 2 years Mean age at baseline= 52 years Postmenopausal Amenorrhea ≥12 months No lipid-altering medication Efficacy at 2 years: Oral E/D – Significant increase in HDL, decrease in LDL & Total cholesterol Transdermal E/D - No consistent change in any of the lipids measured Tibolone – No change in total cholesterol or TGs, increase in LDL-C, decrease in HDL-C
23. LIFT Trial Investigators 2008: N = 4538 Duration = 34 months Results: Tibolone reduced the risk of fracture and breast cancer and possibly colon cancer but increased the risk of stroke in older women with osteoporosis. Danish Osteoporosis Prevention Study 2012: After 10 years of randomized treatment, women receiving MHT early after menopause had a significantly reduced risk of mortality, heart failure, or myocardial infarction, without any apparent increase in risk of cancer, venous thromboembolism, or stroke. Metabolite activity Dydrogesterone’s metabolite (20α-dihydrodydrogesterone) has no estrogenic, androgenic, glucocorticoid, or mineralocorticoid effects.1 The metabolites of tibolone have estrogenic (3 and 3 hydroxytibolone), progestogenic, and androgenic (4 tibolone) properties.2,3 Glucocorticoid activity None with dydrogesterone.4 Tibolone and its metabolites show antagonistic activity at the glucocorticoid receptor.5 (Anti-)mineralocorticoid activity Weak antimineralocorticoid activity with dydrogesterone.4 Tibolone and its metabolites show antagonistic activity at the mineralocorticoid receptor.5 Glucose metabolism While there are no data on the effect of dydrogesterone alone on glucose metabolism, combined estrogen and dydrogesterone MHT given to 32 women reversed menopause-associated changes in insulin secretion and elimination, suggesting that dydrogesterone does not impact the positive effects of estrogen.6 This is further reinforced by a study of 41 postmenopausal women receiving 0.625 mg/day CEE plus 10 mg/day dydrogesterone for 14 days/cycle, which revealed no adverse effect of dydrogesterone on glucose metabolism.7 In postmenopausal women (n=105) receiving tibolone 2.5 mg for 2 years, treatment reduced insulin sensitivity, although glucose levels and glucose tolerance remained unaffected.8 A decrease in insulin sensitivity was observed in a 2 year study of 105 healthy 31 obese postmenopausal women received tibolone 2.5 mg daily.9 Lipid metabolism In women taking dydrogesterone (n=8) for 3 months, no changes in total cholesterol, LDL-C, HDL-C, triglycerides, or any other lipid parameters associated with vascular disease were observed.10 During 2 years of treatment with tibolone 2.5 mg (n=35 postmenopausal women), HDL-C was decreased by 26.8% and there was a non-significant increased in LDL-C.11 References: 1. Rizner T et al. Steroids 2011;76:607–15; 2. Kloosterboer H. J Steroid Biochem Mol Biol 2001;76:231–8; 3. De Gooyer ME et al. Steroids 2003;68:21–30; 4. Schindler AE. Maturitas 2003;46(S1):7–16; 5. Escande A et al. J Steroid Biochem Mol Biol 2009;116:8–14; 6. Godlsland IF et al. Clin Endocrinol 2004;60:541–9; 7. Gelfand MM et al. Menopause 1997;4(1):10–18; 8. Manassiev N et al. Clin Endocrinol (Oxf) 2013;78:297–302; 9. Morin-Papunen L et al. Eur J Endocrinol 2004;150:705–14; 10. Lacey R et al. Br J Clin Pract 1983;24:2–10; 11. Hänggi W et al. Brit J Obs Gyn 1997;104:708–17.