review http://dx.doi.org/10.1590/0004-2730000003021 Female infertility of endocrine origin Infertilidade feminina de origem endócrina Rita Vasconcellos Weiss1, Ruth Clapauch2 ABSTRACT 1 Instituto Estadual de Diabetes Infertility is defined as the failure to conceive, with no contraception, after one year of regular inter- e Endocrinologia Luiz Capriglione course in women < 35 years and after 6 months in women > 35 years. A review on causes, manage- (IEDE); Pontifícia Universidade ment and treatment of endocrine causes of female infertility was performed. Epidemiological data Católica do Rio de Janeiro (PUC- suggest that around 10% to 15% of couples are infertile. Anovulatory problems are responsible from RJ), Rio de Janeiro, RJ, Brazil 2 Laboratory for Clinical and 25% to 50% of causes of female infertility. Advanced age, obesity, and drugs, have a negative effect Experimental Research on Vascular on fertility. Different hypothalamic, pituitary, thyroid, adrenal, and ovarian disorders may affect fertil- Biology (BioVasc), Biomedical ity as well. Infertility is a growing phenomenon in developed societies. We here provide information Center, Universidade do Estado about how to identify endocrine patients with ovulatory dysfunction. Women must be advised about do Rio de Janeiro (UERJ); and Arq Bras Endocrinol Metab. 2014;58(2):144-52 Hospital Federal da Lagoa, limiting factors to be avoided, in order to protect their fertility. Endocrinology Sector, Ministry of Keywords Health, Rio de Janeiro, RJ, Brazil Infertility; infertility causes; infertility propaedeutics; anovulation; ovarian factor RESUMO Correspondence to: A infertilidade é definida como uma falha na concepção, sem anticoncepcionais, após um ano de Rita Vasconcellos Weiss relações sexuais regulares em mulheres com menos de 35 anos e após seis meses em mulheres Av. Ataulfo de Paiva, 135, sala 1014 22440-901 – Rio de Janeiro, RJ, Brazil com mais de 35 anos. Foi feita uma revisão das causas, manejo e tratamento das causas endócrinas [email protected] causadoras de infertilidade feminina. Os dados epidemiológicos sugerem que cerca de 10% a 15% Received on Sept/30/2013 dos casais são inférteis. Os problemas de anovulação são responsáveis por 25% a 50% das causas Accepted on Nov/25/2013 de infertilidade feminina. A idade avançada, a obesidade e as drogas têm um efeito negativo na ferti- lidade. Diferentes transtornos hipotalâmicos, pituitários, tireoideanos, adrenais e ovarianos também podem afetar a fertilidade. A infertilidade é um fenômeno cada vez mais comum nas sociedades de- senvolvidas. Fornecemos aqui informações sobre como identificar pacientes endocrinológicos com disfunções ovulatórias. As mulheres devem ser aconselhadas a evitar fatores limitadores de forma a proteger sua fertilidade. Arq Bras Endocrinol Metab. 2014;58(2):144-52 Descritores Infertilidade; causas de infertilidade; propedêutica da infertilidade; anovulação; fator ovariano INTRODUCTION tors that accounted for female infertility, were ovulatory disorders (25%), endometriosis (15%), pelvic adhesions nfertility is defined as the failure to conceive after (11%), tubal blockage (11%), other tubal abnormalities one year of regular intercourse in women < 35 years I (11 %), and hyperprolactinemia (7%). Other reports de- not using contraception and after six months in women scribe ovulatory disorders as responsible for more than > 35 years (1). Epidemiological data suggest that about half of the causes of female infertility (2). 10% to 15% of all couples will experience difficulties to conceive (primary infertility) or to conceive the num- ber of children they wanted (secondary infertility). INVESTIGATION Based on a survey performed in developed coun- Albeit anovulation accounts for 25% to 50% of the causes tries, the World Health Organization (WHO) estimates of female infertility (2,3), even in women in whom it that female infertility accounts for 37% of causes in in- is highly suspected, like those with irregular cycles, it fertile couples, male infertility for 8% and both – male is important to check tubal patency (usually by means and female infertility – for 35%. Five percent of couples of hysterossalpingography) and endometrial cavity sta- ABE&M todos os direitos reservados. os direitos ABE&M todos © have unexplained infertility and 15% became pregnant tus (by transvaginal ultrassound ou hysteroscopy), as Copyright during the study. The most common identifiable fac- these two are common causes of female infertility. Male 144 Arq Bras Endocrinol Metab. 2014;58/2 Female infertility factors should be promptly investigated by means of at rhea, weight changes and hot flashes should be con- least one spermogram. Assessment of multiple causes is sidered. Physical exam should include polycystic ovary especially important in women of more advanced age, syndrome (PCOS) stigmata, as well as goiter or Turner in which investigation should be shortened in order not syndrome features. Breast and genital examination en- to delay treatment. The main factors to be addressed in sure normal sexual development, and may provide an the infertile couple are presented in figure 1. estimation of estrogenic status. Ovarian fators comprise (i) anovulation, (ii) ovula- One or more of the methods below are employed to tion with luteal insufficiency, when progesterone secre- detect ovulation (6): tion by the corpus luteum is not enough to maintain endometrial stability until HCG production is settled Cervical mucus (4); and (iii) luteinized non-ruptured follicule syn- Women with ovulatory cycles show clear, smooth, slip- drome (LUF), when the follicle develops to its ma- pery mucus of increasing volume when getting closer turity, but remains in the ovary without rupture, and to the mid-cycle (oestrogenic mucus), in parallel to es- there it undergoes luteinization, being able to produce trogen rise and the ovulatory peak. After ovulation, vis- progesterone. In this situation, secretory changes oc- cosity increases and mucus becomes sticky, grainy, and cur in the mucus, and vaginal cytology; and proges- tacky (gestagenic mucus). During the genital exam, it terone levels are consistent with ovulation. Effectively, is possible to collect a sample of the mucus and let it however, no oocyte is released to the tubes. All these dry on a slide to be examined in a microscope at low three modalities will be here referred to as ovulatory magnification: a typical pattern, resembling fern leaves dysfunctions. can be observed in estrogenic mucus. Hypoestrogenic women show little or no mucus Evaluation of the infertile woman during the genital exam, together with a pale mucosa. Anovulatory PCOS patients, on the contrary, show the same pattern of estrogenic mucus all over their cycle. Nowadays, personal devices, which are in fact mini microscopes, using saliva instead of cervical mucus, may act like monitors of the ovulation period. Women seek- ing pregnancy put saliva samples on the device across their cycle. Samples dry and are magnified by the lens, showing the same ferning pattern present in cervical mucus when estrogen levels are high, allowing women to detect their possible period of ovulation. Male factor Limiting factors for mucus analysis in detecting ovu- lation are genital infecctions and LUF, among others. Figura 1. Infertility causes and evaluation. Female causes: (A) Ovarian Hormonal cytology fator; (B) Tubo-peritoneal fator; (C) Uterine fator; (D) Cervical fator. A vaginal Papanicolau stained smear show flat, scat- OVULATION PROPAEDEUTICS tered, and eosinophilic cells in the follicular phase. When ovulation occurs, cells become closer to each History and physical exam other and basophilic. LUF is also a limitation for this Regular cycles, low abdominal pain in the middle of method. the cycle for a few hours and abundant mucus, all sug- gest ovulation. However, up to 10% of women with Basal body temperature these features turn out to be anovulatory (5), or to Progesterone secretion during luteal phase increases have luteal insufficiency. Complete anamnesis, com- body temperature in 0.3 a 0.5 degrees Celsius. How- prising menarchal age, menstrual pattern since the first ever, infections and even stress can alter body tempera- ABE&M todos os direitos reservados. os direitos ABE&M todos two years after menarche, contraceptive use, previous ture as well, making this indirect method also limited © pregnancies and outcomes, hirsutism, acne, galactor- for ovulation confirmation nowadays. Copyright Arq Bras Endocrinol Metab. 2014;58/2 145 Female infertility Hormonal dosages Serial transvaginal ultrassound (US) Blood and urinary dosages may be performed in order to This is the gold standard, most precise method for assess ovulation, in two or more moments of the cycle: the evaluation of ovulation, where direct visualiza- – Early follicular phase (2nd-5th day): FSH and in- tion of follicular development is possible. It is usually hibin B levels may show the likelihood of ovu- performed from the 9-10th day of the cycle up to ovu- lation, especially in older women candidates lar rupture. It is also the only method able to detect for in vitro fertilization (IVF). FSH levels > 10 LUF syndrome. The addition of dopplerfluxometry IU/L are considered predictive of poor preg- elicits corpus luteum evaluation (11). The association nancy outcome, and >18 IU/L were reported between hormonal dosages and US monitoring con- as resulting in no live births (7), the same hap- fers even more accuracy in analyzing anatomical and pening with inhibin B levels