Premature ovarian insufficiency: A hormonal treatment approach.

In vitro fertilization with donor oocytes is the treatment of choice for women with confirmed POI who wish to get pregnant. 8 Patients with Turner syndrome should undergo previous cardiovascular assessment, once pregnancy is relatively contraindicated for these patients (risk of aortic rupture). 8 39 40

Premature ovarian insufficiency (POI) is characterized by loss of ovarian function before the age of 40 years. Diagnosis is based on follicle-stimulating hormone (FSH) levels >25 mIU/mL measured on two occasions (different samples) at least 4 weeks apart. POI is suspected in the presence of irregular menstrual cycles or secondary amenorrhea in women before the age of 40 years, or in girls with primary amenorrhea. Symptoms of hypoestrogenism are usually present, but this not mandatory. Most POI cases are idiopathic, but they may also be due to autoimmune disease, genetic cause, oophorectomy, chemotherapy, radiation therapy (RT), and other less frequent causes. POI is of genetic background in about 10% of cases, most commonly in patients with primary amenorrhea. Chromosomal analysis (Karyotype) is indicated in non-iatrogenic POI cases. In the presence of Y chromosomal material, patients must be submitted to gonadectomy because of the high risk of gonadal tumours. Despite being associated with infertility, spontaneous pregnancy may occur in 5% to 10% of POI cases, Good therapeutic practices include providing guidance on a healthy lifestyle and sexual and psychological assessment and follow-up. Hormonal treatment is mandatory for all POI-women with no contraindication , and it shall be continued until the usual age of menopause.

The assessment of a POI-women requires a detailed history and physical examination seeking for signs of hypoestrogenism and comorbidities that could point to a possible cause. A detailed personal and family history may raise situations associated with POI, such as autoimmune disease and genetic cause. 2 3 In cases of primary amenorrhea either with or without delayed puberty, signs of genetic abnormality must be investigated (i. e., Turner syndrome stigmata, such as short stature, webbed neck, low hairline, and cubitus valgus). It is also necessary to assess the development of secondary sexual characteristics, especially breasts. 2 8 After excluding the possibility of pregnancy, women presenting with irregular menstrual cycles (oligomenorrhea) or secondary amenorrhea should be assessed for a differential diagnosis considering other menstrual disturbances, such as: polycystic ovary syndrome, hyperprolactinemia, hypothalamic or hypophyseal (hypogonadotrophic) amenorrhea and thyroid disease. 2 8 Women may report symptoms of estrogen deprivation, such as vasomotor (hot flushes) and genitourinary (vaginal dryness, urgency and urinary frequency) symptoms. The more acute the condition, the more significant the vasomotor symptoms will be. Changes in mood, sexuality and sleep pattern may be present and interfere negatively in quality of life. 1 2

Despite controversial results in the literature, many women with POI may present low serum testosterone levels when compared to non-POI women of the same age. 24 25 27 28 29 30 31 Although this testosterone deficiency seems to contribute to the manifestation of POI, there is not enough evidence to recommend routine testosterone administration or replacement therapy in these patients. 22 32 Testosterone can be currently prescribed for women with POI diagnosed with hypoactive sexual desire disorder with no contraindication. 33 34 According to the literature, transdermal testosterone adhesive patches delivering 300 mcg/day are associated with an improvement in sexual function, but these are not commercially available in Brazil, being obtained through handling pharmacy. 35 36 37 Evidence suggest that testosterone levels should be used for three to six months with clinical and laboratory reassessment of serum testosterone levels (to verify whether the dose is not supraphysiological). 33 In case there is no clinical response after six months, therapy should be suspended. 33 In case treatment is continued, a clinical (hyperandrogenism signs) and laboratorial (measurement of testosterone levels) reassessment should be conducted every six months. 33 The patient must be informed that there are no safety data on the use of testosterone for over 24 months, as well as there are no approved formulations commercially available in Brazil. 1 33

Once POI diagnosis is established, the patient should receive clear guidance on all repercussions caused by early hypoestrogenism, including compromised fertility. Prolonged estroprogestative HRT is the treatment of choice for POI. It must be individualized according to age, clinical manifestation, and metabolic changes and the patient's preferences must be considered. HRT should be continued at least until 50 years of age, and there is no indication for follow-up with measurement of FSH or estradiol levels. Evidence relative to HRT in women with usual menopause cannot be directly transposed to women with POI. The following general guidance should be provided: adopting a healthy life style in terms of diet and physical exercise and avoiding smoking. Mammograms and oncotic colpocytologies should be conducted under the same indications for women of the general population, while bone densitometry should be considered in the diagnosis of POI with individualized repetition. The aim of POI treatment is to offer an overall improvement in physical, mental and sexual health while simultaneously promoting quality of life. National Specialized Commission on Gynecological Endocrinology of the Brazilian Federation of Gynecology and Obstetrics Associations (FEBRASGO) President: Cristina Laguna Benetti Pinto Vice-President: Ana Carolina Japur de Sá Rosa e Silva Secretary: José Maria Soares Júnior Members: Andrea Prestes Nácul Daniela Angerame Yela Gomes Fernando Marcos dos Reis Gabriela Pravatta Rezende Gustavo Arantes Rosa Maciel Gustavo Mafaldo Soares Laura Olinda Rezende Bregieiro Costa Lia Cruz Vaz da Costa Damásio Maria Candida Pinheiro Baracat Rezende Sebastião Freitas de Medeiros Tecia Maria de Oliveira Maranhão Vinicius Medina Lopes

The most frequent genetic causes are numerical or X chromosome structural abnormalities, such as Turner syndrome and full/partial deletions, translocation, and other abnormalities involving the X chromosome. 2 5 Despite this genetic abnormality profile most frequently presents as primary amenorrhea, it can also manifest as secondary amenorrhea. 9 The fragile X syndrome (the most common cause for inherited mental retardation) is a genetic condition associated with the X chromosome and caused by a mutation of the FMR1 gene. Women presenting with a premutation of the FMR1 gene are at an increased risk of developing POI. Despite its accounting for a small percentage of the genetic causes of POI, this abnormality is present in up to 13% of familial cases. It does not cause mental retardation in the patient who carries it (premutation), but it may lead to the gene’s full mutation in the following generation, which will present with full expression of the syndrome. For this reason, the assessment of POI patients, when detected genetic origin, should also include family genetic counseling. 2 5 Autosomal disorders consist of rare syndromes that may be associated with POI; there is no indication for routine investigation. These may include, but are not limited to, galactosemia, mutation in hormone receptors (LH, FSH), blepharophimosis-ptosis-epicanthusinversus syndrome (BPES) and defects in proteins and enzymes involved in steroidogenesis. 2 3 5

Considering the increased risk for hypoestrogenism-associated diseases, the following general guidance should be provided to women with POI: A healthy lifestyle including resisted exercise (weight lifting), no smoking, and maintenance of proper body weight; Adequate ingestion of calcium and vitamin D (preferably included in their diet, however, if necessary, patient may use supplements); Assessing cardiovascular risks, including blood pressure (at least annually) and lipid panel (every five years); HRT regimen may be adjusted based on clinical response and annual reassessment.

The objectives of POI treatment are symptoms relief and reducing the repercussions of hypoestrogenism. Although vasomotor symptoms (hot flushes) are the main apparent reason for the use of HRT, reasons related to greater morbidity (i.e., bone loss) must be made clear and reinforced to the patient. 19 Psychosocial support should be offered, with special care regarding the reproductive aspects. 1 Estrogen replacement is recommended to maintain bone health, prevent osteoporosis, and reduce the risk of fracture. 1 19 Likewise, the early start of HRT continued until the usual age of menopause has a positive effect on the risk of cardiovascular disease. 1 19 HRT is also beneficial for quality of life and sexual function (Chart 1). 20 18 Source: Adapted from the European Society for Human Reproduction and Embryology (ESHRE) Guideline Group on POI, Webber L, Davies M, Anderson R, et al. ESHRE Guideline: management of women with premature ovarian insufficiency. Hum Reprod. 2016;31(5):926–37. 1 Webber L, Anderson RA, Davies M, Janse F, Vermeulen N. HRT for women with premature ovarian insufficiency: a comprehensive review. Hum Reprod Open. 2017;2017(2):hox007. 19 Committee on Gynecologic Practice. Committee Opinion No. 698: Hormone Therapy in Primary Ovarian Insufficiency. Obstet Gynecol. 2017;129(5):e134–41. 22

It is estimated that about 20% to 30% of POI cases are associated with autoimmune disease. 2 The most frequently involved organ is the thyroid, with Hashimoto’s thyroiditis affecting 14% to 27% of patients with autoimmune involve-ment. 2 Despite showing fair inferior prevalence, the autoimmune conditions of adrenal insufficiency (Addison’s disease) and type 1 diabetes mellitus are also associated with POI; as well assystemic lupus erythematosus, rheumatoid arthritis, pernicious anemia, vitiligo, and Crohn’s disease. 8

POI is a condition caused by loss of ovarian activity before the age of 40 years. 1 It is characterized by irregular menses consisting of prolonged or absent menstrual cycles associated with a reduction in ovarian capacity for producing sex steroids and an increase in gonadotrophins, i.e., a state of hypergonadotrophic hypogonadism. 1 In addition to menstrual disturbance lasting at least four months, POI diagnosis requires elevated FSH levels measured on two occasions at least one month apart. The European Society for Human Reproduction and Embryology (ESHRE) has currently accepted and recommended FSH cutoff value of up to 25 mIU/mL. 1 2 The term “premature ovarian insufficiency” is not universally used. The condition has already been called “early menopause”, “early ovarian failure”, and “premature ovarian failure”. However, its progression is known to be long and variable, with irregular and unpredictable ovulation in 50% of cases and pregnancy in up to 5% to 10%. 3 4 Another variation is “primary ovarian insufficiency”. 1 4 5 Febrasgo suggests the use of the term “premature ovarian insufficiency” and as a preferred terminology. POI prevalence at 35 years of age is of 0.5% and at 40 years of approximately 1%. 6 Frequency seems to vary according to ethnicity: it is more frequent in women of Hispanic and African-American origin (1,4%) and less frequent in Japanese women (0,5%). 7 POI generally occurs after a normal puberty and regular cycles, but in 10% of cases it manifests as primary amenorrhea. 2

Pelvic surgery is the most frequent cause for hormonal deficiency in premenopausal women. 10 POI may be caused by a reduction in ovarian tissue, such as in cystectomy or oophorectomy, or even changes in local blood flow due to surgical procedures such as hysterectomy or tubal ligation (not consensual) and also by local inflammatory processes. 11 ) Many chemotherapeutic drugs are toxic to oocytes and granulosa cells and may cause depletion of the primordial follicles and/or damage to follicle maturation. 12 Regardless of cell cycle stage, cytotoxic alkylating agents are the most frequently associated to gonadal disorders. 13 The mechanism of damage is believed to be a massive destruction of the population of developing follicles. As a consequence, there is a drop in estrogen levels and compensatory elevation in FSH, thereby recruiting a new pool of quiescent follicles that will rapidly be destroyed; this cycle of rapid activation and depletion of the follicular population has been refered to as burn-out . 14 This category of drugs includes cyclophosphamide, ifosfamide, dacarbazine, busulfan, melphalan, and chlorambucil. Procarbazine (derived from an alkylating hydrazine) also shows high gonadal toxicity. 13 15 This phenomenon, which may be transitory, is influenced by patient's age, type of chemotherapy drug and administered dose. The older the patient, the higher the probability of developing POI. 8 13 Oocytes are very sensitive to radiation. Ovarian damage depends on the irradiation fieldand total cumulative dose. 13 POI development post-RT depends on the ovarian reserve available pre-irradiation ; thus, ovarian sensitivity to radiation increases with age. 13 16 Other etiologies of POI—yet of no solid evidence in the literature—are smoking, infections (mumps, rubella, chicken pox, tuberculosis, and malaria), chemicals (such as bromopropane and vinylcyclohexene dioxide), environmental toxins and heavy metals. 11 17

Upon suspected POI, any hormonal treatment must be suspended at least 60 days before FSH measurement. Diagnosis may only be confirmed after two repeated measurements at least 4 weeks apart. Chromosomal analysis (karyotype) must be requested for all non-iatrogenic POIwomen, preferably for those before the age of 30 years. As soon as the diagnosis of POI is made, DXA scan is indicated to assess bone mass and aid in establishing therapeutic recommendations. Adopting a healthy lifestyle including physical activity and maintenance of proper body weight, as well as having a healthy diet with the an adequate calcium intake and avoiding smoking will aid in the prevention of cardiovascular and osteometabolic diseases. Unless contraindicated, the formal recommendation is estrogen replacement therapy with menacme-adjusted doses to improve vasomotor and genitourinary symptoms, maintain bone health, prevent osteoporosis and reduce the risk of fractures, administered until the physiological age of menopause. In patients with an intact uterus, progestagen for endometrial protection must be associated with the estrogen therapy, in a cyclic or continuous regimen. There is no evidence thus far to sustain the use of androgens for all POI patients. In POI women who may present episodic ovulation and do not wish to risk pregnancy, there is a need for the use of contraception. For infertility treatment in POI cases the recommendation is assisted reproductive techniques with donated oocytes. Assessments of sexual function, psychological disorder, sleep quality, and quality of life should be incorporated into clinical practice. Annual clinical follow-up is recommended to verify patients adaptation and adherence to the proposed hormone replacement therapy. However, screening for cancer (cervix, breast, and colon) and metabolic disease should be conducted under the same indications and periodicity as set for women of the general population.