Use of Hormone Replacement Therapy in Special Circumstances.

The term hormone therapy (HT) has been used for decades in conditions resulting from estrogen deficiency also called as estrogen deficient endocrinopathy. Under the umbrella of HT various regimes are used. When it is used after natural menopause to allay, the postmenopausal symptoms it is termed as menopausal hormonal therapy (MHT). After many randomized studies it was understood that its risks outweigh its benefits. These risks included thromboembolic phenomena, cardiovascular diseases, gall bladder diseases, and genital malignancy including breast cancers.[] After surgical menopause, in the absence of uterus and ovaries, estrogen only therapy (ET) is given as HT. On the other hand, progestins are added to estrogen to avoid the risk of endometrial hyperplasia and malignancy, in cases of supracervical hysterectomy, in postoperative case of endometriosis and early stage cancer of endometrium where hysterectomy has not been performed. The term hormone replacement therapy (HRT) is reserved only for premature ovarian insufficiency (POI) and Turner’s syndrome. A large number of studies evaluating the safety of HRT, including women health initiative (WHI) and the million women study challenged its safety and raised the concerns over its usage specially in relation to the risk of cancer.[,] Hence, a debate arose regarding the role of HT and risk of cancers in women using HT. Apart from its risk in association with cancer, other medical conditions such as cardiovascular disease, cognitive dysfunction, Alzheimer disease, stroke and some gynecological conditions including endometriosis, demand the use of HT with caution. EUGONADOTROPIC SITUATIONS Cancer risk with hormone replacement therapy Breast cancer Since the WHI study, it was found that breast cancer risk was more with combined usage of estrogen and progestogen as compared to ET. In a 20-year follow-up of WHI women in estrogen progestin arm had an increased incidence of breast cancer compared to placebo with no significant difference in breast cancer mortality. In the estrogen only arm, there was a lower incidence of breast cancer and breast cancer mortality.[] In large scale, observational studies both estrogen-progestin and estrogen only MHT were associated with increased breast cancer risk and mortality with higher risk among those on estrogen progestin therapy.[,] There are many confounding factors which change the risk associated with breast cancer such as shown in Table 1. Synthetic progestins have more risk compared to micronized progesterone.[] Breast cancer risk is increased by a number of factors, HT being one of them [Table 1]. Starting hormone therapy in breast cancer survivors Survivors of breast cancer are not usually prescribed HT because of the risk of recurrence.[] In spite of increased risk of recurrence sometimes it becomes necessary to prescribe HT in severely symptomatic women. In treated women, there are certain facts which are to be remembered. Breast cancer is hormone-dependent tumor and depends on estrogen. When breast cancers have estrogen receptors (ERs), they are known as ER + ve. Estrogen can stimulate the growth of these tumors. These ER + ve cases are treated both by antiestogen and other drugs such as tamoxifem or anastrozole. These agents have been useful in metastatic breast cancer without any effect on menopausal symptoms Most oncologists have refuted the use of HT in women treated for breast cancer but in certain cases HT might be indicated specially with severe osteoporosis or hot flashes. The cases of recurrent breast cancer are selected for HT when they have small primary tumor and there is no involvement of lymphnodes.[] Some clinical trials have been done although in small numbers to substantiate this view point. This has led to the use of HT in selected cases. There are other nonhormonal prescriptions and medications to prevent osteoporosis, hotflashes, and vaginal dryness. These include phytoestrogens, gabapentin, and venalafexime. Endometrial cancer It is significantly decreased with continuous combined regime that is conjugated estrogen and medroxyprogesterone acetate.[] It is recommended that woman with uterus should take concomitant estrogen progestin therapy.[] The factors which play the role of producing endometrial carcinoma are shown in Table 2. The other risk factors for endometrial cancer include woman who have taken tamoxifen for more than 2 years they have increased chances of endometrial cancer by 2.3–7.5 fold increased in relative risk.[] Lifetime risk of endometrial cancer is about 60% in women with hereditary nonpolyposis colorectal carcinoma [Table 2].[] Hormone therapy in endometrial cancer survivors Older women developing endometrial cancer after having menopause may not require HT as they are usually asymptomatic but younger women who undergo surgery manifest symptoms due to surgical menopause. For survivors after surgical treatment of endometrial cancer use of estrogen always increases the risk of recurrence. The studies are limited and no conclusive evidence has been derived.[] Colorectal cancer The risk of colorectal cancer is decreased up 44% in woman using MHT.[] After an average intake of MHT for 15 years, there was an reduction of 10% in colorectal cancer and on further analysis a higher reduction (36%) was seen with estrogen progestin use as compared to 26% with estrogen only use [Table 3]. Risk of hormone therapy with ovarian cancer Reports on this subject are discrepant. Cancer research UK has summarized that ovarian cancer risk increases with intake of HT but after stoppage of HT the risk returns to normal in few years.[] After further analysis, it was found that ET is associated with higher risk of ovarian cancer as compared to combined preparations. Table 3 depicts the relationship of ovarian cancer with HT according to the National Cancer Institute Study. Another reports from Danish National Cancer Registry revealed that HT users (both estrogen as well combined preparations) for more than 8 years had increased incidence of serous and endometroid tumors but decreased risk of mucinous tumors.[] Hormone therapy in ovarian cancer survivors Premenopausal women treated surgically for ovarian carcinoma can safely be offered estrogen therapy, especially who are moderate–to-severe symptomatic. A study was reported that posttreatment HT does not have any negative effect on the progression free interval and overall survival of epithelial ovarian cancer patients. However, more studies are needed to substantiate this view. CORRELATION OF HORMONE THERAPY WITH OTHER CANCERS Hormone therapy with cervical cancer While there is known association between oral contraceptive usage and cervical cancer, no association has been documented between HT and cervical cancer. Squamous cell carcinoma of cervix is not an estrogen dependent tumor. No case of recurrence has been reported in squamous cell carcinoma survivors but studies have shown that adenocarcinoma may recur with HT.[] Risk of hormone therapy with other cancers Neither combined nor estrogen only HT has been found to be associated with increased risk of lung cancer, skin cancer, and other site cancer. However, WHI results are contradictory.[] HORMONE REPLACEMENT THERAPY IN CERTAIN MEDICAL CONDITIONS Hormone therapy and its use in coronary artery disease Risk of coronary artery disease (CAD) in premenopausal women is less as compared to age matched male because of protective effect of estrogen, however after 60 years risk of CAD matches with that of male. Another observation in men is that men have CAD because of epicardial and endothelial dysfunction where as women have more of microvascular diseases.[] Added risk factors for CAD in women are obesity, history of preeclampsia, gestational diabetes, autoimmune diseases, and metabolic syndrome. Theoretically estrogen has protective effect on cardiac function through acting favorably of lipid profile and other cardiac functions. With this theory, it has been observed that HT is associated with 50% reduction in CAD and overall mortality in menopausal women. However, WHI Research study came out with big surprises that in actual HT increased CAD risk by 29%, risk of stroke by 41% and twofold increase in risk of venous thromboembolism. Later in 2012, WHI itself published a comprehensive report which stated that systemic HT till 60 years of age have more beneficial effects.[] In another study, it was postulated that HT reduces the incidence of CAD by around 50% if commenced within 10 years of menopause. This is referred as window-of-opportunity for primary prevention.[] The timing hypothesis Despite of the findings of cardiovascular disease (CHD) and stroke among participants in WHI HT trials and subsequent analysis support the timing hypothesis. It says that the risk of MHT differs according to the age of initiation of MHT and time since menopause. There is correlation of the CHD risk with age of initiation of MHT 63 versus 51 years. Furthermore, there is a higher risk of CHD with higher dose of estrogen.[] In a 13 year follow-up, it concluded in WHI study that woman who entered younger than 60 years with only estrogen therapy had lower risk of CHD as compared to combined therapy.[] Similarly, in an 18-year follow-up a woman aged 50–59 in either group had reduced risk of mortality.[] More recent data from randomized controlled trials, ELITE study[] Kronos, Longevity Research Institute[] and KEEPS study investigated the effect of MHT started early or late and correlated with the onset of atherosclerosis. In KEEPS study women had slow progression of atherosclerosis.[,] As far as stroke was concerned, it was directly proportional to late age of starting MHT but no clear trends were observed. Cognitive impairment Initial results were positive on cognition by MHT but further study shows that estrogen has verse effect on cognition compared to ET.[] Timing hypothesis applied like WHI KEEP ELITE and trials.[] This infers that HT should be given to healthy postmenopausal women before they undergo atherosclerotic changes in their intima. HT should not be given in women who have already suffered from myocardial infarction, stroke and pulmonary embolism. To summarize CAD risk in menopausal women can be divided into two groups one with nonmodifiable risk factors, i.e. is age and family history and the other with modifiable risk factors such as smoking, obesity, and a sedentary life style. The subset of symptomatic young menopausal women should be discussed about beneficial role of HT at least for 6–10 years for their menopausal symptoms, which will also help to reduce the risk of CAD working as primary prevention. However, in older age group, especially with a history of prior CAD, there is no role of HT as secondary prevention. Role of hormone therapy in senile dementia of Alzheimer type Dementia is defined as progressive decline in intellectual and cognitive function. Causes are of three types: Due to systemic illness where brain is affected Local cause like a brain tumor Due to degenerative disease of nervous system the example being senile dementia of Alzheimer type (SDAT) this being the most common. The management of any type of dementia is prevention by early screening and cause related management. The role of HT in prevention of dementia is controversial. Several studies have suggested that HT prevents SDAT but did not improve established disease.[] However, the data from large double-blind placebo controlled studies have a negative finding for it as a preventive role. Even in WHI memory study it was found that increased rates of dementia with HT. This was mainly in women above the age of 75 years. Hence, there are mixed findings on the effect of HT on SDAT. Based on this current view, HT is not recommended for the prevention of SDAT. HT use in younger women around the time of menopause lowers the risk of SDAT but in women aged 65–79 years instead of decreased risk, there is increased risk of Alzheimer by 1–3/1000. HT on cognition has not posed any substantial benefit, but in cases of surgical menopause, ET may have some beneficial effect. HORMONE THERAPY FOR OTHER MEDICAL CONDITIONS (OPTIONAL) Corticosteroid usage Corticosteroids are used in treatment of diseases such as collagen disease, asthma, inflammatory bowel disease, and chronic active hepatitis. As these diseases affect predominantly women, HT to prevent osteoporosis becomes an important issue. In rheumatoid arthritis, HT has shown an improvement in symptom of the disease,[,] as it improves disease-associated osteoporosis. Systemic lupus erythematosus This disease is strongly linked with estrogen, i.e. it starts with menarche and abates with menopause. Despite this fact HT does not flare up lupus.[] To summarize, women on corticosteroid receiving HT have an advantage as it prevents osteoporosis.[] Liver disorders and hormone therapy HT is contraindicated in acute liver disease. However, once the episode of acute illness is passed HT can be initiated by transdermal route.[] In chronic liver disease, impaired liver function is a metabolic contraindication to the use of estrogen. However, in cholestatic liver disease and chronic liver disease, there is more risk of osteoporosis. HT can be given in these selected cases by transdermal route which is safe for these chronic liver disease patients.[] Thrombotic phenomenon HT is contraindicated in acute episode of venous thromboembolic episode (VTE) as the patient is at high risk of repeat VTE episode. In selected cases, where there is recognized risk factor for VTE low-dose HT can be given with close monitoring.[] The current use of HT is associated with increased risk of VTE but not in past users.[] In postmenopausal women with a history of VTE it seems not so innocuous to use HT as previously thought. In cases of superficial thrombophlebitis estrogens can be safely used whereas contrary to this study previously there were contradictory reports. Hormone therapy with gall bladder disease Currently, it is understood that any type of oral HT increases the risk of any gall bladder event. Risk factors for developing gall bladder cancer include female gender, ethnicity, cholelithiasis, age, chronic inflammatory conditions, biliary problems and gall bladder polyp.[] Researchers have found that transdermal route of HT is less likely to cause any disease as compared to oral form which is metabolized through liver and reaches gall bladder to cause harm. Role of hormone therapy in women with endometriosis (in specific gynecological disease) Endometriosis is defined as the presence of functional endometrial tissue (stroma and glands) outside the uterine cavity that has a tendency toward invasion and infiltration. Being an estrogen-dependent disease, endometriosis tends to undergo regression and/or reactivation based upon the levels of estrogen. Reactivation of the disease caused by exogenous estrogen is not only a concern after surgical menopause but endometroid tissue can undergo malignant transformation after exogenous HT especially with estrogen intake alone. There are two types of ERs alpha and ER beta (ERβ). These receptors can have different types of action on different tissues. Endometrial cells have over expression of (ERβ) and under expression of progesterone receptors. Along with this fact these receptors vary in density from person to person and from cell to cell. The definitive treatment of endometriosis remains radical surgery inform of total hysterectomy and bilateral salpingo-oophorectomy. If done in perimenopausal women, it causes iatrogenic menopause which necessitates HRT to alleviate symptoms till the natural age of menopause. However, the main concern with HT after pelvic clearance for endometriosis is the potential risk of reactivation or malignant transformation of residual endometriotic foci due to exposure to exogenous estrogen. The reoperation rate for recurrent endometriosis varies from 8% to 19%.[,] There has been reported incidence of extra pelvic endometriosis.[] Since the estrogen only HT causes more risk of reactivation and malignant transformation of residual endometriosis various societies have recommended continuous combined HT (estrogen and progestin) in these women till the natural age of menopause.[,] However, enough evidence is still lacking about the optimal regime, dose and years of use. To conclude, it should be discussed with each patient. Just because she has had surgery for endometriosis and she is symptomatic, she should not be denied a continuous combined regime of HT to allay her symptoms. The safe progestogen is micronized progestogen which is body friendly and is derived from Yam root. Recently it has been reported that adding progestogen in postoperative case of endometriosis does not protect from recurrence. Estrogen only HT is as safe as combined HT in well selected cases where complete surgical clearance for endometrial tissue has been done. MANDATORY USE OF HORMONE REPLACEMENT THERAPY Hypergonadotropic–Hypogonadism Turner syndrome (TS) – TS defines phenotypic females who have one x chromosome and complete or partial absence of the second chromosome. It is characterized by hypergonadotropic hypogonadism due to gonadal dysgenesis resulting in primary or secondary amenorrhea. These girls when investigated had low levels of anti-mullerian hormone (AMH), undetectable inhibin B, elevated levels of follicle-stimulating hormone (FSH), and luteinizing hormone (LH).[,] The treatment for TS is tailored by estrogen replacement therapy first, for induction of puberty and then for maintaining secondary sex characters attaining peak bone mass and maintaining uterine growth for possible pregnancy later. The primary goal in the treatment of TS is attainment of puberty and maintenance of feminization for which estrogen is the best mode of therapy. Among the oral preparation of estrogen, the most commonly used is conjugated equine estrogen.[] Initiation of treatment begins at 11–12 years, if levels of gonadotropin are elevated and AMH concentration is low. LH and FSH levels may be measured yearly starting from the time of initiation of therapy. If LH and FSH levels are found to be normal, spontaneous puberty can be expected. It is important to balance out treatment in TS for feminization by estrogen by growth hormone for gaining height. As sometimes, estrogen treatment may cause early closure of epiphysis and delay growth potential. The use of progestins in TS – Patients of TS have normal uterus anatomically. Therefore, after 2 years of estrogen treatment cycle progestins have to be added to avoid break through bleeding, endometrial hyperplasia and cancer.[] Micronized progesterone is safest.[] There is no need to monitor LH and FSH levels in girls of TS during estrogen therapy as the levels remain elevated in agonadal women until very high doses of estrogen is given.[] Maintenance of bone health and prevention of fractures is very crucial in management of TS by estrogen therapy whether given by transdermally or orally. Effect on social interaction and neurocognitive behavior can be studied in TS. Estrogen therapy could improve motor speed, verbal and nonverbal processing.[] Early attainment of growth and puberty had a positive influence on self-esteem and social adjustment.[] Primary ovarian insufficiency Primary ovarian insufficiency (POI) is characterized by high levels of FSH and low levels of estrogen with absent or irregular menstrual cycles. Many of the health complications accompany POI, i.e. increased risk of stroke, breast, osteoporosis and cardiovascular diseases.[] HRT usually should continue till the natural age of menopause. The etiologies of POI are multiple, namely genetic, autoimmune, iatrogenic related to chemoradiations and surgery and spontaneous presentations. Effects of POI on various systems of body - the attainment of early menopause increases risk of all postmenopausal symptoms. If POI occurs before 30 years, i.e. before attainment of peak bone mass, fracture risk increases substantially.[] Bone mineral density increases maximum with early initiation of HRT. In women with POI, it was observed that they have a higher risk of CAD and cardiovascular mortality, probably due to reduced vascular endothelial function and atherosclerosis. Treatment with HRT for 6 months improved endothelial function.[] The role of estrogen deficiency in the development of depression is controversial as the depression is heightened more by the vasomotor symptoms.[] Women with POI do not respond traditional fertility treatments. Though there is a small chance of conception with sperm, ova or embryo donation with the help of assisted reproductive techniques, the main treatment option is adoption. Ideal therapy for these women is the one which delivers estradiol by a routine which is most physiological and does not cause systemic side effects as the treatment has to be given for a very long period of time. It has been observed that transdermal patch or vaginal ring that delivers 0.100 µg is adequate for hormone replacement. The equivalent dose given by oral route is associated with complications due to 1st pass metabolism in liver.[] Oral contraceptives have typically 1 week pill-free period resulting in a regular estrogen deficient state in which unwanted menopausal symptoms may appear. Compared to oral contraceptives, transdermal HRT also have more physiologic effects on blood pressure, renal functions and other symptoms. Cyclic progestins are recommended in these patients for protection against endometrial carcinoma. The regime for this purpose is usage of 100 µg of transdermal estradiol/day with medroxyprogesterone acetate 10 mg for 12 days in a month. This causes complete secretory changes in endometrium.[]

HRT besides being useful in alleviating vasomotor symptoms, genitourinary symptoms, and symptoms arising due to osteoporosis, has an extended role also upon improvement of quality of life. Conditions which were previously thought as an absolute contraindication to HRT, such as cancers, endometriosis, CAD, liver, and gall bladder diseases VTE, and autoimmune diseases, the extensive researches have shown good response to therapy in these conditions. After a detailed discussion with the patient, HT can be offered in well selected cases after optimizing the dose, compound, and duration of therapy. Just on the basis of a preexisting medical condition, a severely symptomatic women should not be denied from the benefits of treatment. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.

1 Hickey M, Elliott J, Davison SL. Hormone replacement therapy. BMJ 2012;344:e7632 Rossouw JE, Anderson GL, Prentice RL, LaCroix AZ, Kooperberg C, Stefanick ML, et al. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: Principal results from the Women's health initiative randomized controlled trial. JAMA 2002;288:321 333 Beral V Million Women Study Collaborators. Breast cancer and hormone-replacement therapy in the million women study. Lancet 2003;362:419 274 Chlebowski RT, Anderson GL, Aragaki AK, Manson JE, Stefanick ML, Pan K, et al. Association of menopausal hormone therapy with breast cancer incidence and mortality during long-term follow-up of the Women's health initiative randomized clinical trials. JAMA 2020;324:369 805 Beral V, Peto R, Pirie K, Reeves G. Menopausal hormone therapy and 20-year breast cancer mortality. Lancet 2019;394:11396 Collaborative Group on Hormonal Factors in Breast Cancer. Type and timing of menopausal hormone therapy and breast cancer risk: Individual participant meta-analysis of the worldwide epidemiological evidence. Lancet 2019;394:1159 687 Eden J. The endometrial and breast safety of menopausal hormone therapy containing micronised progesterone: A short review. Aust N Z J Obstet Gynaecol 2017;57:12 58 Holmberg L. Hormonal replacement therapy for women with a personal history of breast cancer?. Ann Oncol 1996;7:655 69 Feeley KM, Wells M. Hormone replacement therapy and the endometrium. J Clin Pathol 2001;54:435 4010 Manson JE, Chlebowski RT, Stefanick ML, Aragaki AK, Rossouw JE, Prentice RL, et al. Menopausal hormone therapy and health outcomes during the intervention and extended poststopping phases of the Women's health initiative randomized trials. JAMA 2013;310:1353 6811 Faubion SS, Crandall CJ, Davis L, El Khoudary SR, Hodis HN, Lobo RA, et al. The 2022 hormone therapy position statement of The North American Menopause Society. Menopause 2022;29:767 9412 Cuzick J, Forbes JF, Sestak I, Cawthorn S, Hamed H, Holli K, et al. Long-term results of tamoxifen prophylaxis for breast cancer –96-month follow-up of the randomized IBIS-I trial. J Natl Cancer Inst 2007;99:272 8213 Watson P, Vasen HF, Mecklin JP, Järvinen H, Lynch HT. The risk of endometrial cancer in hereditary nonpolyposis colorectal cancer. Am J Med 1994;96:516 2014 National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology Uterine Neoplasms 1. Fort Washington PA: National Comprehensive Cancer Network 201015 Chlebowski RT, Wactawski-Wende J, Ritenbaugh C, Hubbell FA, Ascensao J, Rodabough RJ, et al. Estrogen plus progestin and colorectal cancer in postmenopausal women. N Engl J Med 2004;350:991 100416 HT and Cancer, Cancer Research UK 2013. Available from: https://www.cancerresearchuk.org17 Panay N, Hamoda H, Arya R, Savvas M British Menopause Society and Women's Health Concern. The 2013 British Menopause Society and Women's Health Concern recommendations on hormone replacement therapy. Menopause Int 2013;19:59 6818 Lacey JV Jr, Brinton LA, Barnes WA, Gravitt PE, Greenberg MD, Hadjimichael OC, et al. Use of hormone replacement therapy and adenocarcinomas and squamous cell carcinomas of the uterine cervix. Gynecol Oncol 2000;77:149 5419 Moyer VA U. S. Preventive Services Task Force. Menopausal hormone therapy for the primary prevention of chronic conditions: U. S. Preventive Services Task Force recommendation statement. Ann Intern Med 2013;158:47 5420 Han SH, Bae JH, Holmes DR Jr, Lennon RJ, Eeckhout E, Barsness GW, et al. Sex differences in atheroma burden and endothelial function in patients with early coronary atherosclerosis. Eur Heart J 2008;29:1359 6921 Crawford SL, Crandall CJ, Derby CA, El Khoudary SR, Waetjen LE, Fischer M, et al. Menopausal hormone therapy trends before versus after. 2002: Impact of the Women's Health Initiative study results. Menopause 2018;26:588 9722 Manson JE, Aragaki AK, Rossouw JE, Anderson GL, Prentice RL, LaCroix AZ, et al. Menopausal hormone therapy and long-term all-cause and cause-specific mortality: The Women's Health Initiative randomized trials. JAMA 2017;318:927 3823 Hodis HN, Mack WJ, Henderson VW, Shoupe D, Budoff MJ, Hwang-Levine J, et al. Vascular effects of early versus late postmenopausal treatment with estradiol. N Engl J Med 2016;374:1221 3124 Miller VM, Naftolin F, Asthana S, Black DM, Brinton EA, Budoff MJ, et al. The Kronos Early Estrogen Prevention Study (KEEPS): What have we learned?. Menopause 2019;26:1071 8425 Gleason CE, Dowling NM, Wharton W, Manson JE, Miller VM, Atwood CS, et al. Effects of hormone therapy on cognition and mood in recently postmenopausal women: Findings from the randomized, controlled KEEPS-cognitive and affective study. PLoS Med 2015;12:e100183326 Henderson VW, St John JA, Hodis HN, McCleary CA, Stanczyk FZ, Shoupe D, et al. Cognitive effects of estradiol after menopause: A randomized trial of the timing hypothesis. Neurology 2016;87:699 70827 Zandi PP, Carlson MC, Plassman BL, Welsh-Bohmer KA, Mayer LS, Steffens DC, et al. Hormone replacement therapy and incidence of Alzheimer disease in older women: The cache county study. JAMA 2002;288:2123 928 Hall GM, Daniels M, Huskisson EC, Spector TD. A randomised controlled trial of the effect of hormone replacement therapy on disease activity in postmenopausal rheumatoid arthritis. Ann Rheum Dis 1994;53:112 629 MacDonald AG, Murphy EA, Capell HA, Bankowska UZ, Ralston SH. Effects of hormone replacement therapy in rheumatoid arthritis: A double blind placebo-controlled study. Ann Rheum Dis 1994;53:54 730 Yell JA, Burge SM. The effect of hormonal changes on cutaneous disease in lupus erythematosus. Br J Dermatol 1993;129:18 2231 Eastell R. Management of corticosteroid-induced osteoporosis. UK consensus group meeting on osteoporosis. J Intern Med 1995;237:439 4732 Motashaw ND, Dave S. Controversies in hormone replacement therapy Krishna UR, Shah D Menopause, obstetrics and gynecology in perspective. Madras: Orient Longman 1996;100 833 Clements D, Compston JE, Evans WD, Rhodes J. Hormone replacement therapy prevents bone loss in patients with inflammatory bowel disease. Gut 1993;34:1543 634 Whitehead MI, Godfree VA. Hormone Replacement Therapy: Your Questions Answered. Churchill Livingstone and Alexander Bolton 199235 Daly E, Vessey MP, Hawkins MM, Carson JL, Gough P, Marsh S. Risk of venous thromboembolism in users of hormone replacement therapy. Lancet 1996;348:977 8036 Stinton LM, Shaffer EA. Epidemiology of gallbladder disease: Cholelithiasis and cancer. Gut Liver 2012;6:172 8737 Shakiba K, Bena JF, McGill KM, Minger J, Falcone T. Surgical treatment of endometriosis: A 7-year follow-up on the requirement for further surgery. Obstet Gynecol 2008;111:1285 9238 Rizk B, Fischer AS, Lotfy HA, Turki R, Zahed HA, Malik R, et al. Recurrence of endometriosis after hysterectomy. Facts Views Vis Obgyn 2014;6:219 2739 Gemmell LC, Webster KE, Kirtley S, Vincent K, Zondervan KT, Becker CM. The management of menopause in women with a history of endometriosis: A systematic review. Hum Reprod Update 2017;23:481 50040 Hamoda H BMS Medical Advisory Council. British Menopause Society tools for clinicians: Progestogens and endometrial protection. Post Reprod Health 2022;28:40 641 Becker CM, Bokor A, Heikinheimo O, Horne A, Jansen F, Kiesel L, et al. ESHRE guideline: Endometriosis. Hum Reprod Open 2022 2022;hoac00942 Hagen CP, Main KM, Kjaergaard S, Juul A. FSH, LH, inhibin B and estradiol levels in Turner syndrome depend on age and karyotype: Longitudinal study of 70 turner girls with or without spontaneous puberty. Hum Reprod 2010;25:3134 4143 Lunding SA, Aksglaede L, Anderson RA, Main KM, Juul A, Hagen CP, et al. AMH as predictor of premature ovarian insufficiency: A longitudinal study of 120 turner syndrome patients. J Clin Endocrinol Metab 2015;100:E1030 844 Rosenfield RL, Perovic N, Devine N, Mauras N, Moshang T, Root AW, et al. Optimizing estrogen replacement treatment in turner syndrome. Pediatrics 1998;102:486 845 Fournier A, Berrino F, Clavel-Chapelon F. Unequal risks for breast cancer associated with different hormone replacement therapies: Results from the E3N cohort study. Breast Cancer Res Treat 2008;107:103 1146 Devineni D, Skee D, Vaccaro N, Massarella J, Janssens L, LaGuardia KD, et al. Pharmacokinetics and pharmacodynamics of a transdermal contraceptive patch and an oral contraceptive. J Clin Pharmacol 2007;47:497 50947 Ostberg JE, Storry C, Donald AE, Attar MJ, Halcox JP, Conway GS. A dose-response study of hormone replacement in young hypogonadal women: Effects on intima media thickness and metabolism. Clin Endocrinol (Oxf) 2007;66:557 6448 Ross JL, Roeltgen D, Feuillan P, Kushner H, Cutler GB Jr. Effects of estrogen on nonverbal processing speed and motor function in girls with Turner's syndrome. J Clin Endocrinol Metab 1998;83:3198 20449 Bannink EM, Raat H, Mulder PG, de Muinck Keizer-Schrama SM. Quality of life after growth hormone therapy and induced puberty in women with turner syndrome. J Pediatr 2006;148:95 10150 Anasti JN, Kalantaridou SN, Kimzey LM, Defensor RA, Nelson LM. Bone loss in young women with karyotypically normal spontaneous premature ovarian failure. Obstet Gynecol 1998;91:12 551 Kalantaridou SN, Naka KK, Papanikolaou E, Kazakos N, Kravariti M, Calis KA, et al. Impaired endothelial function in young women with premature ovarian failure: Normalization with hormone therapy. J Clin Endocrinol Metab 2004;89:3907 1352 Cohen LS, Soares CN, Vitonis AF, Otto MW, Harlow BL. Risk for new onset of depression during the menopausal transition: The Harvard study of moods and cycles. Arch Gen Psychiatry 2006;63:385 9053 Canonico M, Oger E, Plu-Bureau G, Conard J, Meyer G, Lévesque H, et al. Hormone therapy and venous thromboembolism among postmenopausal women: Impact of the route of estrogen administration and progestogens: The ESTHER study. Circulation 2007;115:840 554 Gibbons WE, Moyer DL, Lobo RA, Roy S, Mishell DR Jr. Biochemical and histologic effects of sequential estrogen/progestin therapy on the endometrium of postmenopausal women. Am J Obstet Gynecol 1986;154:456 61