Review and Recommendations on Management of
Adult Female Thalassemia Patients with Hypogonadism based on Literature
Review and Experience of ICET-A Network Specialists
Vincenzo De Sanctis1, Ashraf T. Soliman2, Heba Elsedfy3, Alice Albu4, Soad Al Jaouni5, Salvatore Anastasi6, Maria Grazia Bisconte7, Duran Canatan8, Soteroula Christou9, Shahina Daar10, Salvatore Di Maio11, Mohamed El Kholy3, Doaa Khater12, Mohamed Elshinawy13 ,Yurdanur Kilinc14, Roberto Mattei15, Hala H. Mosli16, Alessandra Quota17, Maria Grazia Roberti18, Praveen Sobti19, Saif AL Yaarubi20, Saveria Canpisi21 and Christos Kattamis22
1 Pediatric and Adolescent Outpatient Clinic, Quisisana Hospital, Ferrara, Italy.
2 Department of Pediatrics, Division of Endocrinology, Hamad General Hospital Doha, Qatar and Department of Pediatrics, Division of Endocrinology, Alexandria University Children's Hospital, Alexandria, Egypt.
3 Department of Pediatrics, Ain Shams University, Cairo, Egypt.
4 Endocrinology and Diabetes Department of Elias Hospital, Carol Davila University of Medicine and Pharmacy, Bucharest, Romania.
5 Head Division of Pediatric Hematology Oncology, Deputy Chair of Hematology & Head Section of Hematology Research Lab, King Fahd Medical Research Center Department of Hematology Faculty of Medicine, King Abdulaziz University Jeddah, Kingdom of Saudi Arabia.
6 Thalassemia Unit, Maternal and Child Department, Garibaldi Hospital, Catania, Italy.
7 Thalassemia Unit, Cosenza, Italy.
8 Director of Thalassemia Diagnosis Center of Mediterranean Blood Diseases Foundation Antalya, Turkey.
9 Thalassemia Unit, Nicosia, Cyprus.
10 Department of Haematology, College of Medicine and Health Sciences, Sultan Qaboos University, Sultanate of Oman & Visiting Scholar, Stellenbosch Institute for Advanced Study (STIAS), Wallenberg Research Centre at Stellenbosch University, Stellenbosch 7600, South Africa.
11 Emeritus Director in Pediatrics, Children's Hospital "Santobono-Pausilipon", Naples, Italy.
12 Department of Pediatrics, Endocrinology Unit, Alexandria University Children's Hospital, Egypt and Child Health Department, Sultan Qaboos University Hospital, Muscat, Sultanate of Oman.
13 Department of Pediatrics, Hematology Unit, Faculty of Medicine, University of Alexandria, Egypt and Child Health Department, Sultan Qaboos University Hospital, Muscat, Oman.
14 Çukurova University, Medical Faculty, Department of Pediatric Hematology, Adana, Turkey.
15 Pediatric Unit, Adria, Italy.
16 Internal Medicine, Endocrinology and Metabolism, Department of Medicine King Abdulaziz University, Jeddah, Kingdom of Saudi Arabia.
17 Thalassemia Unit, Gela, Italy.
18 Immunohematology and Blood Bank Unit, OORR Foggia, Italy.
19 Pediatric Hemato-Oncology Unit , Christian Medical College and Hospital, Ludhiana Punjab, India.
20 Head of Pediatric Endocrine Unit, Department of Child Health, Sultan Qaboos University Hospital, Al-Khoud, Sultanate of Oman.
21 Thalassemia Unit, Umberto 1° Hospital, Siracusa, Italy
22 First Department of Paediatrics, University of Athens, Athens, Greece.
Received: August 20, 2016
Accepted: November 14, 2016
Mediterr J Hematol Infect Dis 2017, 9(1): e2016060, DOI 10.4084/MJHID.2017.001
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Background: Multi-transfused thalassemia major (TM) patients frequently develop severe endocrine complications, mainly due to iron overload, anemia, and chronic liver disease, which require prompt diagnosis, treatment and follow-up by specialists.
The most common endocrine complication documented is hypogonadotropic hypogonadism which increases with age and associated comorbidities. It is thus important for physicians to have a clear understanding of the pathophysiology and management of this disorder. Also to be aware of the side effects, contraindications and monitoring of sex steroid therapy. In this paper, practical ICET-A recommendations for the management of hypogonadism in adult females with TM are addressed.
Methods: In March 2015, the Coordinator of the International Network of Clinicians for Endocrinopathies in Thalassemia and Adolescent Medicine (ICET-A) conducted a two-step survey to assess the attitudes and practices of doctors in the ICET-A network taking care of adult female TM patients with hypogonadism. They were clinically characterized by the absence of pubertal development or discontinuation or regression of the maturation of secondary sex characteristics, and biochemically by persistent low FSH, LH and estradiol levels. Recently a supplementary survey on adult female hypogonadism in TM was undertaken within the ICET-A network.
Results: The completed questionnaires were returned by 16 of 27 specialists (59.2%) following 590 female TM patients over the age of 18 years; 315 patients (53.3%) had hypogonadism, and only 245 (74.6%) were on hormone replacement therapy (HRT). Contraceptive oral pills (COC) were the first treatment choice in 11 centers (68.7%). A wide range of COCs was used with different progestin contents. In general, the patients’ compliance to treatment was reported as good in 81.2% of centers. The frequency of required tests for follow-up HRT, in addition to the regular check-up for thalassemia, was variable in the participating centers.
Conclusions: Doctors taking care of TM patients should have sound knowledge of the pathophysiology of hypogonadism in adult females with TM. They should know the potential effects of HRT including advantages and disadvantages of estrogen and progestins. Moreover, they should keep in consideration the emotional needs of these patients dreaming of attaining a full pubertal development.
The most common endocrine complication documented in adult TM patients is hypogonadotropic hypogonadism which increases with age and the associated comorbidities. In adult females TM patients, hypogonadism is clinically diagnosed by the absence of pubertal development, or discontinuation or regression of the maturation of secondary sex characteristics due to pituitary dysfunction and/or gonadal damage, secondary to iron overload. The incidence rate of hypogonadism, in both sexes, varies considerably between countries and much more between specialized centers, ranging from around 50% and may even approach 100%.[1-4]
Evidence suggests that more severe defects are related to a higher rate of iron loading possibly due to increased vulnerability to free radical toxicity.[1-4]
Hormone replacement therapy (HRT) in females with hypogonadism aims to alleviate symptoms of estrogen deficiency and prevent long-term complications such as osteoporosis. However, HRT has been linked to various risks and the debate regarding its risk-benefit ratio continues. The principal risks of HRT are thromboembolic disease, stroke, cardiovascular events, gallbladder disease, breast cancer and endometrial hyperplasia or endometrial cancer.
In March 2015, the Coordinator (VDS) of the International Network of Clinicians for Endocrinopathies in Thalassemia and Adolescent Medicine (ICET-A) conducted a two-step survey to assess the attitudes and practices of doctors taking care of adult TM with hypogonadism. In this report, we present the results of the study and the practical recommendations for hypogonadism in adult females with TM based on literature review and the experience of specialists of ICET-A network. Where possible, the recommendations are based on and linked to, the evidence that supports them, unless good-quality evidence is absent.
Materials and Methods19196677
The second step survey was administered online to the ICET-A members on July 4th, 2016. An introductory letter explained the purpose of the study. The questionnaire consisted of 23 questions, namely: personal doctors’ data, place of work, specialization, number of female patients with TM followed over the age of 18 years, number of TM patients on HRT, type/s of HRT used, the patients' compliance to treatment, the speciality of the physician recommending HRT, opinions on indications and contraindications for HRT use among doctors and types and number of tests used during patients' follow-up.
After collection and analysis of data, the ICET-A Steering Committee (VDS, ATS, HE, MEK, SDM, CK) prepared (third step) practical recommendations for the management of these patients. In making these recommendations, experts considered the differences in countries’ facilities, general cost of tests and recommended management of hypogonadism. The ICET- A members were asked to provide comments on the accuracy, feasibility, and approval of the recommendations.
Twelve different formulations and three routes of administration for HRT were used. The majority of respondents (33.3%) used ethinyl estradiol 30 µg/drospirenone 3 mg as first-line treatment choice, (25%) ethinyl estradiol 20 µg/drospirenone 3 mg. Ethinyl estradiol 35 µg/cyproterone acetate 2 mg (41.6%) and ethinyl estradiol 20 µg/drospirenone 3 mg (29.1%) were reported as second-line treatment choice. Transdermal patch, estradiol transdermal plus progesterone, and etonogestrel/ethinyl estradiol vaginal ring were used and recommended by 16.6%, 4.1%, and 4.1%, respectively.
Second step: The questionnaires were returned by 16 of 27 specialists: 6 pediatric endocrinologists, 2 endocrinologists; 3 pediatric hematologists, 3 hematologists, 1 pediatrician and 1 general practitioner [the majority (75%) were female doctors] following 590 female TM patients over the age of 18 years; 315 (53.3%) had hypogonadism, and 245 (74.6%) were on HRT.
The reported most common contraindications to treatment were: elevation of liver enzymes - from 3 to 6 times the normal values (62.5%), thrombophilia (43.7%), insulin dependent diabetes (25%), insulin dependent diabetes associated with vascular complications (6.2%), patient non-compliance to treatment (25%). HRT was recommended by endocrinologists in 9 thalassemia centers, by endocrinologists and gynecologists in 6, and by endocrinologist and hematologist in 1 center. Responders were asked to select the three commonest compounds used as HRT. Contraceptive oral pills (COC) were the first choice of treatment in 11 centers. A wide range of COCs was used with different progestin contents, such as drospirenone, dydrogesterone, norgestrel, norethisterone, gestodene, desogestrel, medroxyprogesterone acetate, micronized progesterone soft gelatin capsules. In 6 Centres transdermal estrogen patch in combination with oral progesterone was given as the first choice of treatment. In general, patients' compliance to treatment was reported as good in 81.2% of Centres.
The frequency and number of required tests during follow-up, in addition to the regular check-up for thalassemia, varied in the participating Centres (even in centers within the same country). The results for each Centre participating in the survey are reported in Table 1.
|Table 1. Frequency of required tests during follow-up of TM patients with hypogonadism on HRT.|
Third step: The ICET-A recommendations for hypogonadism in adult females with TM were based on published, peer-reviewed scientific evidence, expert opinion, and accumulated professional knowledge and experience of ICET-A network specialists. Recommendations from published guidelines were used when available and appropriate. Original articles for the evidence-based recommendations were obtained following a computer search for ‘hormone replacement’ as a keyword and also in combination with ‘venous thrombosis’ (VTE) or ‘deep venous thrombosis’ (DVT) or ‘pulmonary embolism’ or ‘thrombophilia’ or "chronic liver disease" or "diabetes" applied to Medline.
The ICET-A Network also issued expert consensus opinions on topics for which limited or low-level evidence was available in the literature. Since not all published references were based on randomized controlled trials, the recommendations have been scored according to the following criteria:
A. High confidence indicates that further research is unlikely to change the confidence in the estimate of effect (●●●)
B. Moderate confidence indicates that further research may change the confidence in the estimate of effect (●●○)
C. Low confidence indicates that further research would likely have a significant impact on the confidence in the estimate of effect (●○○)
D. Insufficient indicates that the evidence is unavailable or does not permit a conclusion (○○○)
Few trials of the effects and complications of estrogen therapy in primary and secondary hypogonadism of women at premenopausal age have been published and none of TM patients. As a consequence of the scanty evidence, recommendations for HRT in thalassemia are based on publications on the effects and complications of COC used for contraception and postmenopausal hormone replacement in healthy women.
The three forms of estrogen produced in the human body are estrone (E1), estradiol (E2) and estriol (E3). The estrogen composition in the female body is approximately 3% estrone, 7% estradiol, and 90% estriol. The potencies of these hormones vary, with estradiol being the most potent followed by estrone and estriol.[6,8]
Sequential estrogen-progestogen replacement therapy is the mainstay of treatment for women with hypogonadism. Estrogen may be replaced using oral, micronized, vaginal, or transdermal preparations. Subcutaneous implants and more recently, nasal sprays and injectable estrogen preparations are also available.
There are three types of estrogen available for hormone replacement: estradiol, ethinylestradiol (a synthetic estrogen, EE) and conjugated equine estrogens (derived from pregnant mare urine, CEE). Major characteristics that differentiate one formulation from another include the form of estrogen used and its dosage, and the generation of the progestin.
The formulations of COC have changed over the past 50 years. The dose of the EE component has decreased from the original 100-150 μg to 15 to 30 μg. These changes were made to lower the risk of thromboembolic complications associated with the use of oral contraceptive pills.
In the absence of a consensus regarding the ideal hormonal replacement regimen for women facing a premature cessation of ovarian function, the estroprogestative substitution commonly involves either HRT or COC prescription.
Several studies compared estrogen preparations in adult females, but the adolescent and young adult population are relatively understudied.[9-12] A recent report in girls with Turner syndrome demonstrated more physiologic estrogen concentrations with the use of the transdermal estrogen preparation versus oral preparations. Ninety percent of the EE is absorbed from the upper gastrointestinal tract in 1 to 2 hours, then exposed to oxidation. Following absorption, EE is metabolized during passage through the enterohepatic circulation. EE has a strong hepatic impact related to its 17a-ethinyl group. This group prevents the inactivation of the EE and results in a slow metabolism and prolonged tissue retention. EE is much more potent than the naturally secreted estrogens because it remains in the blood for a longer time after administration and has a greater effect on the liver.
In our survey, the majority of specialists (11 centers) preferred COCs as the first line of treatment COCs of convenience, efficacy and patients’ preference and availability.
COC are classified into different generations (first, second, third and fourth), depending on the time of introduction into the market. They vary regarding the dose of estrogen and the type of progestin. Progestins are needed to avoid an unopposed estrogen effect and maintain endometrial health. Progestins can be administered via the oral, transdermal (as a patch), or intra-uterine routes. Micronized progestogens are available to use orally, vaginally and as transdermal (cream) preparations.
Progestins have no selectivity for the various steroid receptors. The first progestins developed were medroxyprogesterone acetate (MPA) and norethisterone enanthate (NET-EN). Shortly after, these were followed by its first derivative norethisterone acetate (NET-A). Many more synthetic progestins have been developed in the following years. We now have second, third and fourth-generation progestins. Examples are levonorgestrel (LNG, 2nd generation), gestodene (GES, 3rd generation), and drospirenone (DRSP), dienogest (DNG) and trimegestone (TMG), all fourth generation. The third-generation progestins have minimal impact on blood glucose levels, plasma insulin concentrations, and the lipid profile. Thus, they are suitable for use in patients with lipid disorders or diabetes.[9-11]
Contrary to menopausal women, adolescents and young female adults with hypogonadism due to other pathologic mechanisms as in TM patients, the HRT treatment is extremely complex because of associated comorbidity (iron overload, the presence of thrombophilic status, chronic liver disease, impaired glucose tolerance or diabetes and cardiovascular disease). In addition, the long- term duration of chelation treatment and psychosocial patients’ needs enhance the difficulty of the management.[1-4,14-18]
Taher et al. reported in a retrospective multicentre study, that thromboembolic events (TE) occurred in a clinically relevant proportion (1.65%) of 8,860 thalassemia patients (75.3% with TM). Thromboembolic events were 4.38 times more frequent in thalassemia intermedia (TI) than in TM patients (p < 0.001). More venous events occurred in TI and more arterial events took place in TM.
A survey, done in 9 Italian thalassemia Centres, disclosed that 32 patients out of a total of 735 (683 with TM and 52 TI), had VTE episodes corresponding to an incidence of 3.95% and 9.61%, respectively. Localization of TE varied; the main one (16/32) involved the central nervous system.
Patients with TE events presented a higher incidence of associated organ dysfunction, such as cardiomyopathy, diabetes, liver function anomalies, and hypothyroidism than those without TE events (50 vs. 13.8%, p <0.05).
Haghpanah and Karimi conducted an electronic search on PUBMED (MEDLINE), SCOPUS, and Google Scholar databases up to January 2011. Out of 152 thalassemic patients with cerebral thromboembolic events; 48% were splenectomized. Nine TM patients had diabetes. Activated protein C resistance, decreased protein C or protein S or plasminogen level were detected in 8 patients. Inadequate transfusion was reported to increase the risk of thrombosis secondary to increased release of pro-coagulant red cell particles.
Oral administration of EE leads to pharmacologic concentration of the hormone in the portal vein before it is metabolized by the liver. This first-pass reaction results in an increased hepatic production of several hormone binding globulins, clotting factors, lipoproteins and angiotensinogen. This increase in VTE risk is highest during the first year of use. It may vary according to the different characteristics of COCs, such as estrogen dose, molecule, and type of progestins. Whether the type of estrogen molecule is associated with different degree of risk for venous thrombosis remains controversial.[19,20]
Based on the Women’s Health Initiative (WHI) trials, oral conjugated equine estrogen and 2.5 mg MPA increased VTE compared with placebo (RR, 2.06; CI, 1.57–2.70). These findings, however, require confirmation.[21,22]
Newer generation formulations of hormonal contraceptives seem to be more thrombogenic than those of second-generation.[19,20,22] Using LNG as the reference , VTE rate ratios for other progestins were: NET-EN0.98, desogestrel 1.82, GES 1.86, DRSP 1.64 and cypropterone (CPA) 1.88.[19,20,22]
Some observational studies assessed the risk of VTE associated with transdermal estrogen therapy in non-thalassemic population. The pro-thrombotic effects seem to be circumvented by transdermal administration of estrogen and, therefore, have significant clinical implications.
The VTE risk for vaginal ring or patch is as high as for COCs of third or fourth generation.
Liver dysfunction in thalassemics is mainly attributable to liver siderosis and chronic HCV infection (chronic hepatitis C).[23,24] Furthermore, chronic hemolysis in TM favours the development of bilirubin gallstones. The incidence of gallstones varies considerably in clinical studies and is related to age and the efficiency of transfusion treatment of studied cohorts. Thirty percent of 858 consecutive Italian TM patients had chololithiasis diagnosed by abdominal ultrasonography or a history of cholecystectomy. In addition, chronic application of third generation progestogens as contraceptives or HRT could influence the serum lipid profile, and consequently increase the risk of biliary lithogenicity.
Although elevation of liver enzymes - from 3 to 6 times the normal values was the commonest contraindication to hormonal treatment reported by 10/16 Centres, further studies including liver imaging and LIC assessment are needed to clarify the role of HRT on liver enzyme levels, metabolic variables and liver fat content.
Insulin dependent diabetes (IDDM) and impaired glucose tolerance (IGT) are relatively common complications in thalassaemia major (ΤΜ) patients with iron overload and sub-optimal chelation therapy. The prevalence of IDDM and IGT in adolescents and young adults with TM mainly treated with desferrioxamine mesylate (DFO) varies considerably in 2 studies ranging from 0 to 21% and from 9.3 to 24.3%, respectively.[27,28] Even higher differences exist in other studies depending on the age composition and on the efficiency of chelation of the studied TM cohorts.
Currently, there appear to be wide variations in the way that professionals evaluate the risk-benefit equation in subjects with IDDM, and significant differences in prescribing practice have been identified. In women with insulin-dependent or non–insulin-dependent diabetes COCs use have limited effect on daily insulin requirements and no effect on long-term diabetes control or progression to retinopathy, if clinical and metabolic monitoring can be ensured. COCs must be avoided in case of, cardiovascular disease or severe microvascular complications such as nephropathy with proteinuria or active proliferative retinopathy.[29-33]
The safety of prescription of COCs to women with type II diabetes is unclear, but a supervised program similar to that of IDDM patients is recommended.
Conclusions and Recommendations
The United States Medical Eligibility Criteria (US MEC) for Contraceptive Use, in July 2016, recommended the following medical eligibility criteria categories for estrogen/progestin pill, hormonal patch and combined vaginal ring:
1 = A condition for which there is no restriction for the use of the contraceptive method.
2 = A condition for which the advantages of using the method generally outweigh the theoretical or proven risks.
3 = A condition for which the theoretical or proven risks usually outweigh the advantages of using the method.
4 = A condition that represents an unacceptable health risk if the contraceptive method is used.
No restrictions are reported for estrogen/progestin pill, patch or vaginal ring in TM patients (category 1). Regarding some other pathologies, the US MEC for the contraceptive use, reported the following risk categories: an increased risk in the presence of family history (1st-degree relatives) for venous thrombosis (category 2) and a high risk in presence of past TE and known thrombogenic mutations (e.g., factor V Leiden; prothrombin mutation; and protein S, protein C, and antithrombin deficiencies) (category 4); in women with chronic hepatitis, COC use does not increase the rate or severity of cirrhotic fibrosis, nor does it increase the risk for hepatocellular carcinoma (category 1); a small increased risk for asymptomatic gallbladder disease (category 2), in subjects with gallbladder disease treated medically the risk is higher (category 3); in women with insulin-dependent or non–insulin-dependent diabetes COC use have limited effect on daily insulin requirements and no effect on long-term diabetes control or progression to retinopathy (category 1), in presence of associated nephropathy, retinopathy, or neuropathy the risk is high (category 4); for atherosclerotic cardiovascular diseases (e.g. smoking, diabetes, hypertension, low HDL, high LDL, or high triglyceride levels) the risk is high (category 3/4); in subjects with migraine without aura or with aura the risk category is 2 and 4, respectively.
On deciding to treat a hypogonadal TM woman with estrogen and progestin, consideration must be given to the general condition of the patient, current chelation therapy and the presence of associated complications.[34-36]
To minimise the potential risks of treatment, excessively high sex hormonal concentrations should be avoided. The aim is to achieve, in regularly menstruating women the typical mean serum estradiol levels of approximately 100 pg/ml (400 pmol/l). Transdermal administration of 25-50 µg 17β estradiol generally produces in TM patients a plasma E2 value in the early to mid-follicular phase range (100-300 pmol/l). Progesterone is usually given at for 12-14 days each month to bring on a menstrual withdrawal bleed. Micronized progesterone is composed of smaller particles that may aid in absorption. It was proposed as first-line progestin because there are reasons to believe that natural progesterone might be safer for the cardiovascular system (no adverse lipid effects) and possibly the breast, although the strongest evidence for endometrial protection is for oral cyclical combined treatment.[34,35,37-39]
The potential effects of HRT demand that doctors taking care of TM patients have a sound knowledge of the benefits and disadvantages of estrogens and progesterone. They must also possess comprehensive knowledge of female reproductive biology and particular sensitivity to the emotional needs of these patients. Current guidelines in patients with premature ovarian failure suggest that therapy should be continued until the average age of menopause (age 50 to 51 years) to prevent premature bone loss, coronary heart disease, and stroke.[40,41]
Because HRT in patients with chronic diseases is a complex task, the ICET-A prepared some relative recommendations for HRT in TM patients and its monitoring (Tables 2 and 3), based on the data reported in the literature for adolescent and young women without TM, for HRT with sex steroids. Further research consortia are needed to investigate these important questions, and to assist clinicians in making the best possible health care approach for the adolescents and young women with TM and hypogonadism.
|Table 2. The ICET-A recommendations for female TM patients with hypogonadism.|
|Table 3. The ICET-A guidelines for the monitoring of HRT in female TM patients with hypogonadism.|
AcknowledgementsWe wish to express our sincere thanks to dr. Ploutarchos Tzoulis, Department of Endocrinology, Whittington Hospital, University College London, London, UK for taking part in the second step survey promoted by ICET-A.
- De Sanctis V, Elsedfy H, Soliman AT, Elhakim IZ,
Soliman NA, Elalaily R, Kattamis C. Endocrine profile of ß-thalassemia
major patients followed from childhood to advanced adulthood in a
tertiary care center. Indian J Endocrinol Metab. 2016;20:451-459 https://doi.org/10.4103/2230-8210.183456 PMid:27366710 PMCid:PMC4911833
- De Sanctis V, Elsedfy H, Soliman AT, Elhakim IZ, Kattamis C, Soliman NA, Elalaily R. Clinical and Biochemical Data of Adult Thalassemia Major patients (TM) with Multiple Endocrine Complications (MEC) versus TM Patients with Normal Endocrine Functions: A long-term Retrospective Study (40 years) in a Tertiary Care Center in Italy. Mediterr J Hematol Infect Dis. 2016 Apr 12;8(1):e2016022. doi: 10.4084/MJHID.2016.022. eCollection 2016. https://doi.org/10.4084/mjhid.2016.022
- De Sanctis V, Soliman AT, Candini G, Elsedfy H. The recommendation of the International Network of Clinicians for Endocrinopathies in Thalassemia and Adolescent Medicine for the assessment of growth hormone secretion in thalassemia.Indian J Endocrinol Metab. 2015;19:306-307 https://doi.org/10.4103/2230-8210.149331 PMid:25729702 PMCid:PMC4319280
- Tiosano D, Hochberg Z.Endocrine complications of thalassemia. J Endocrinol Invest. 2001;24:716-723. https://doi.org/10.1007/BF03343916 PMid:11716158
- Gallagher JC. Effect of early menopause on bone mineral density and fractures. Menopause 2007;14:567–571 https://doi.org/10.1097/gme.0b013e31804c793d PMid:17476146
- No author listed. The Writing Group for the Women's Health Initiative. Risks and benefits of estrogen plus progestin in healthy postmenopausal women. JAMA 2002; 288: 321-333. https://doi.org/10.1001/jama.288.3.321 PMid:12117397
- De Sanctis V, Solimam AT, Elsedfy H, Di Maio S. Current practice in treating adult female thalassemia major patients with hypogonadism: An International Network of Clinicians for Endocrinopathies in Thalassemia and Adolescence Medicine survey from Italy. Indian J Endocrinol Metab.2016 Nov-Dec;20(6):880-881. https://doi.org/10.4103/2230-8210.192905 PMid:27867897 PMCid:PMC5105578
- Andersson KK, Kappas A. Hormones and liver function. In: Schiff L, Schiff ER, editors. Diseases of the liver. Philadelphia: JB Lippincott; 1982. p. 167–235.
- Batur P, Bowersox N, McNamara M. Contraception: Efficacy, Risks, Continuation Rates, and Use in High-Risk Women. J Womens Health (Larchmt). 2016 Aug;25(8):853-6. doi: 10.1089/jwh.2016.5942. https://doi.org/10.1089/jwh.2016.5942
- De Leo V, Musacchio MC, Cappelli V, Piomboni P, Morgante G. Hormonal contraceptives: pharmacology tailored to women's health Hum Reprod Update. 2016 Sep;22(5):634-46. doi: 10.1093/humupd/dmw016. https://doi.org/10.1093/humupd/dmw016
- Nelson AL. An update on new orally administered contraceptives for women. Expert Opin Pharmacother. 2015;16: 2759-2772. https://doi.org/10.1517/14656566.2015.1100173 PMid:26512437
- Divasta AD, Gordon CM. Hormone replacement therapy and the adolescent Curr Opin Obstet Gynecol. 2010;22:363-368. https://doi.org/10.1097/GCO.0b013e32833e4a35 PMid:20724926
- Torres-Santiago L, Mericq V, Taboada M, Unanue N, Klein KO, Singh R, Hossain J, Santen RJ, Ross JL, Mauras N: Metabolic effects of oral versus transdermal 17beta-estradiol (E2): a randomized clinical trial in girls with Turner syndrome. J Clin Endocrinol Metab. 2013, 98:2716–2724. https://doi.org/10.1210/jc.2012-4243 PMid:23678038
- Moratelli S, De Sanctis V, Gemmati D, Serino ML, Mari R, Gamberini MR, Scapoli GL. Thrombotic risk in thalassemic patients. J Pediatr Endocrinol Metab. 1998;11 (Suppl 3): 915-921. PMid:10091165
- Borgna Pignatti C, Carnelli V, Caruso V, Dore F, De Mattia D, Di Palma A, Di Gregorio F, Romeo MA, Longhi R, Mangiagli A, Melevendi C, Pizzarelli G, Musumeci S. Thromboembolic events in beta thalassemia major: an Italian multicenter study. Acta Haematol. 1998; 99:76-79. https://doi.org/10.1159/000040814 PMid:9554453
- Michaeli J, Mittelman M, Grisaru D, Rachmilewitz EA. Thromboembolic complications in beta thalassemia major. Acta Haematol. 1992;87:71-74. https://doi.org/10.1159/000204720 PMid:1585774
- Taher A, Isma'eel H, Mehio G, Bignamini D, Kattamis A, Rachmilewitz EA, Cappellini MD. Prevalence of thromboembolic events among 8,860 patients with thalassaemia major and intermedia in the Mediterranean area and Iran. Thromb Haemost. 2006; 96:488-491. https://doi.org/10.1160/th06-05-0267
- Haghpanah S, Karimi M. Cerebral thrombosis in patients with ß-thalassemia: a systematic review. Blood Coagul Fibrinolysis. 2012;23:212-217. https://doi.org/10.1097/MBC.0b013e3283502975 PMid:22322139
- Hugon-Rodin J, Gompel A, Plu-Bureau G. Epidemiology of hormonal contraceptives-related venous thromboembolism. Eur J Endocrinol. 2014;171:R221-230. https://doi.org/10.1530/EJE-14-0527 PMid:25012200
- Maitrot-Mantelet L, Hugon-Rodin J, Canonico M. Hormonal contraceptives and venous thromboembolism: an epidemiological update. Best Pract Res Clin Endocrinol Metab. 2013;27:25-34. https://doi.org/10.1016/j.beem.2012.11.002 PMid:23384743
- Cushman M, Kuller LH, Prentice R, Rodabough RJ, Psaty BM, Stafford RS, Sidney S, Rosendaal FR; Women's Health Initiative Investigators. Estrogen plus progestin and risk of venous thrombosis. JAMA. 2004;292:1573-1580. https://doi.org/10.1001/jama.292.13.1573 PMid:15467059
- Santen RJ, Allred DC, Ardoin SP, Archer DF, Boyd N, Braunstein GD, Burger HG, Colditz GA, Davis SR, Gambacciani M, Gower BA, Henderson VW, Jarjour WN, Karas RH, Kleerekoper M, Lobo RA, Manson JE, Marsden J, Martin KA, Martin L, Pinkerton JV, Rubinow DR, Teede H, Thiboutot DM, Utian WH; Endocrine Society. Postmenopausal hormone therapy: an Endocrine Society scientific statement. J Clin Endocrinol Metab. 2010;95(7 Suppl 1):s1-s66 https://doi.org/10.1210/jc.2009-2509 PMid:20566620
- Prati D, Capelli C, Silvani C, De Mattei C, Bosoni P, Pappalettera M, Mozzi F, Colombo M, Zanella A, Sirchia G. The incidence and risk factors of community-acquired hepatitis C in a cohort of Italian blood donors. Hepatology. 1997; 25:702-704. https://doi.org/10.1002/hep.510250335 PMid:9049222
- Prati D, Zanella A, Farma E, De Mattei C, Bosoni P, Zappa M, Picone A, Mozzi F, Rebulla P, Cappellini MD, Allain JP, Sirchia G. A multicenter prospective study on the risk of acquiring liver disease in anti-hepatitis C virus negative patients affected from homozygous beta-thalassemia. Blood.1998; 92:3460-3464. PMid:9787188
- Origa R, Galanello R, Perseu L, Tavazzi D, Domenica Cappellini M, Terenzani L, Forni GL, Quarta G, Boetti T, Piga A. Cholelithiasis in thalassemia major Eur J Haematol. 2009; 82:22-25 https://doi.org/10.1111/j.1600-0609.2008.01162.x PMid:19021734
- Sieron D, Czerny B, Sieron-Stoltny K, Karasiewicz M, Bogacz A, Seremak-Mrozikiewicz A, Kotrych D, Boron D, Mrozikiewicz P. The effect of chronic estrogen application on bile and gallstone composition in women with cholelithiasis. Minerva Endocrinol. 2016;41:19-27. PMid:25413941
- Cunningham MJ, Macklin EA, Neufeld EJ, Cohen AR. Thalassemia Clinical Research Network. Complications of beta-thalassemia major in North America. Blood 2004;104:34-39 https://doi.org/10.1182/blood-2003-09-3167 PMid:14988152
- De Sanctis V, Soliman AT, Elsedfy H, Pepe A, Kattamis C, El Kholy M, Yassin M. Diabetes and Glucose Metabolism in Thalassemia Major: An Update. Expert Rev Hematol. 2016;9:401-408 https://doi.org/10.1586/17474086.2016.1136209 PMid:26697756
- Gourdy P. Diabetes and oral contraception. Best Pract Res Clin Endocrinol Metab. 2013;27:67-76. https://doi.org/10.1016/j.beem.2012.11.001 PMid:23384747
- Suthipongse W, Taneepanichskul S. An open-label randomized comparative study of oral contraceptives between medications containing 3 mg drospirenone/30 microg ethinylestradiol and 150 microg levonogestrel/30 microg ethinylestradiol in Thai women. Contraception 2004;69:23–26. https://doi.org/10.1016/j.contraception.2003.08.014 PMid:14720615
- Godsland IF, Gangar K, Walton C, Cust MP, Whitehead MI, Wynn V, Stevenson JC. Insulin resistance, secretion, and elimination in postmenopausal women receiving oral or transdermal hormone replacement therapy. Metabolism. 1993;42:846-853. https://doi.org/10.1016/0026-0495(93)90058-V
- Mueck AO. Hormone replacement therapy for internal risk patients. Gynakol Geburtshilfliche Rundsch. 2006;46:174-190. https://doi.org/10.1159/000095726 PMid:17068402
- CDC. U.S. medical eligibility criteria for contraceptive use, 2016. MMWR Recomm Rep 2016; 65 (No. RR-3):55-80.
- Bergendal A, Kieler H, Sundström A, Hirschberg AL, Kocoska-Maras L. Risk of venous thromboembolism associated with local and systemic use of hormone therapy in peri- and postmenopausal women and in relation to type and route of administration. Menopause 2016; 23:593-599. https://doi.org/10.1097/GME.0000000000000611PMid:27023862
- North American Menopause Society. The 2012 hormone therapy position statement of: The North American Menopause Society. Menopause 2012; 19:257-271. https://doi.org/10.1097/gme.0b013e31824b970a PMid:22367731 PMCid:PMC3443956
- Katz M, De Sanctis V, Vullo C, Wonke B, McGarrigle HH, Bagni B. Pharmacokinetics of sex steroids in patients with beta thalassaemia major. J Clin Pathol. 1993;46:660-664. https://doi.org/10.1136/jcp.46.7.660 PMid:8157756 PMCid:PMC501398
- Baber RJ, Panay N, Fenton A; IMS Writing Group. 2016 IMS Recommendations on women's midlife health and menopause hormone therapy. Climacteric. 2016;19:109-150. https://doi.org/10.3109/13697137.2015.1129166 PMid:26872610
- Picardo E, Mitidieri M, Minniti E, Ambroggio S, D'Addato F, Benedetto C, Gregori G, Baù MG. The first case of breast cancer in thalassemic patient: case report and review of literature. Gynecol Endocrinol. 2015;31:345-348. https://doi.org/10.3109/09513590.2014.998646 PMid:25578420
- Bawa R, Matemavi P, Maizlin I, Sung KJ. Ductal carcinoma in-situ in Turner syndrome patient undergoing hormone replacement therapy: A case report. Int J Cancer Ther Oncol. 2016; 4(1):4113. DOI: 10.14319/ijcto.41.13 https://doi.org/10.14319/ijcto.41.13
- van Kasteren YM, Schoemaker J. Premature ovarian failure: a systematic review on therapeutic interventions to restore ovarian function and achieve pregnancy. Hum Reprod Update. 1999 ;5 :483-492. https://doi.org/10.1093/humupd/5.5.483 PMid:10582785
- Nelson LM. Clinical practice. Primary ovarian insufficiency. N Engl J Med. 2009;360:606-614. https://doi.org/10.1056/NEJMcp0808697 PMid:19196677 PMCid:PMC2762081
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