Hyperandrogenic States in Pregnancy
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Physiol. Res. 60: 243-252, 2011 https://doi.org/10.33549/physiolres.932078 REVIEW Hyperandrogenic States in Pregnancy N. KAŇOVÁ1, M. BIČÍKOVÁ1 1Institute of Endocrinology, Prague, Czech Republic Received September 6, 2010 Accepted October 8, 2010 On-line November 29, 2010 Summary during pregnancy are almost always the result of a Hyperandrogenic states in pregnancy are almost always the result condition that arises over the course of the pregnancy, of a condition that arises during pregnancy. The onset of virilization since a high level of androgens that occurs before symptoms is often very fast. The mother is protected against conception causes anovulation and leads to infertility. hyperandrogenism by a high level of SHBG, by placental aromatase The clinical symptoms of hyperandrogenism and a high level of progesterone. The fetus is protected from the during pregnancy are not different from those during non- mother’s hyperandrogenism partly by the placental aromatase, that pregnancy. This most frequently leads to an occurrence of transforms the androgens into estrogens, and partly by SHGB. hirsutism in androgen-dependent areas of predilection, Nevertheless there is a significant risk of virilization of the female such as the upper lip, chin, linea alba, groin, thigh and fetus if the mother’s hyperandrogenic state is serious. The most chest. There is often acne on the face, shoulders, back and frequent cause of hyperandrogenic states during pregnancy are chest. With some women there occurs hair loss with pregnancy luteoma and hyperreactio luteinalis. Hormonal ensuing hair thinning in the temporoparietal area. During production is evident in a third of all luteomas, which corresponds pregnancy we relatively frequently see the rapid onset of to virilization in 25-35 % of mothers with luteoma. The female masculine symptoms such as clitoromegaly and fetus is afflicted with virilization with two thirds of virilized mothers. deepening voice caused by a larger larynx. Some Hyperreactio luteinalis is created in connection with a high level of hyperandrogenic symptoms are fully reversible, such as hCG, e.g. during multi-fetus pregnancies. This condition most acne and hair loss. On the contrary, hirsutism, deepening frequently arises in the third trimester, virilization of the mother voice and clitoromegaly are only partially reversible. occurs in a third of cases. Virilization of the fetus has not yet been Therapy for these symptoms is possible only after described. The most serious cause of hyperandrogenism is removing the causes of hyperandrogenism. Laser represented by ovarian tumors, which are fortunately rare. treatment is currently used to treat hirsutism. In addition to phoniatric care, the vocal chords can be operated on to Key words rectify a deep voice. Hirsutism • Hyperandrogenemia • Virilism • Luteoma • Cyst Physiological changes of androgens during Corresponding author pregnancy N. Kaňová, Institute of Endocrinology, Národní 8, 116 94 Prague 1, Czech Republic. E-mail: [email protected] During pregnancy extensive changes take place in the mother's organism that enables the successful development of the fetus. The high level of estrogens Introduction causes an increase in protein synthesis in liver and with it an increase in specific binding proteins such as sex The incidence of hyperandrogenic states during hormone-binding globulins (SHGB), whose level rises pregnancy is relatively low. Hyperandrogenic states from the beginning of the pregnancy. PHYSIOLOGICAL RESEARCH • ISSN 0862-8408 (print) • ISSN 1802-9973 (online) © 2011 Institute of Physiology v.v.i., Academy of Sciences of the Czech Republic, Prague, Czech Republic Fax +420 241 062 164, e-mail: [email protected], www.biomed.cas.cz/physiolres 244 Kaňová and Bičíková Vol. 60 Fig. 1. Estrogens in the placenta. During pregnancy the synthesis of binding; less than five percent from the total amount is dehydroepiandrosterone (DHEA) in the adrenal glands bound to SHBG (DHEA, androstenedione and estriol). increases significantly. Its sulphate (DHEAS) is the main Due to the high binding of strong androgens during precursor of the synthesis of steroid hormones in the pregnancy the level of free, biologically effective placenta, which is why the plasmatic level of both of androgens during hyperandrogenism remains without these androgens drops by nearly half during pregnancy change for a long time. (Milewich et al. 1978). Due to the increased level of Another factor is the aromatase cytochrome SHBG from the start of pregnancy there occurs a change P 450 present in the placenta. The placenta is fully in the ratio of the free and bound testosterone. The level equipped to deal with enzymes, allowing for the synthesis of the free testosterone is due to the higher binding to of steroid hormones. In the human placenta there is not SHBG up to the 28th week of pregnancy lower than expressed the steroid 17α-hydroxylase (CYP17), during non-pregnancy; then, however, it rises and peaks therefore C21 steroids cannot be converted to C19 steroids in the third trimester (Rivarola et al. 1968, Milewich et in trophoblast. Besides the above-mentioned aromatase a al. 1978, Barbieri 1999). Feedback set for levels of free basic role is played by the placental steroid sulfatase, testosterone leads to increased production of testosterone 3β-hydroxysteroid dehydrogenase (3β HSD), so that the total testosterone at the end of the first 17β-hydroxysteroid dehydrogenase (17β HSD) and trimester reaches levels common with men. others. As a precursor of the synthesis of steroid hormones in the placenta, there is used Protection of the mother from excess of dehydroepiandrosterone sulfate (DHEAS), whose source androgens during pregnancy is partly the fetal adrenal glands and to a lesser degree the mother's adrenal glands. DHEAS is desulfurylated by An excess of androgens produces lower clinical steroid sulfatase. Free DHEA is converted by 3β HSD manifestations during pregnancy than with non-pregnant and 17β HSD to androstenedione and testosterone, women. The main reason is the high level of SHBG respectively. Androstenedione is converted by placental which is able to bind most sex hormones. Affinity is aromatase to estrone which is converted by 17β HSD to greatest with dihydrotestosterone (DHT) that is bound estradiol. These estrogens pass over the placental barrier from 59 %. This is followed by testosterone (44 %), to the mother’s circulation and the fetus where liver estradiol (19.6 %) and estrone (7.4 %). The remaining uptake occurs. Enzymatic apparatus in fetal liver create steroids have a very weak and therefore insignificant estriol, which is the main pregnancy estrogen that is, after 2011 Hyperandrogenemia and Pregnancy 245 crossing over the placental barrier to the mother's fetus; on the contrary severe hyperandrogenism causes circulation, it is filtered through the kidneys and gets into malformation of the genitalia in this period as well. Other urine in high levels (Fig. 1). Thanks to this it can be used factors (such as functionality of the placental aromatase), as an indicator of the function of the fetal-placental unit of which some are unknown, also influence whether in pregnancy. During a successful pregnancy its level virilization of the female fetus occurs. rises smoothly up to the time of birth. Under normal circumstances aromatization of the androgens require Etiology of hyperandrogenic states in only roughly 1 % functional capacity of placental pregnancy aromatase. If the mother’s organism or the fetus is flooded with androgens, the functional capacity of this 1/ Ovarian – tumor enzyme increases in significance. – non-tumor Last but not least, a high level of progesterone 2/ Adrenal – tumor contributes to the reduction of the clinical manifestation – non-tumor of hyperandrogenism during pregnancy. This competes 3/ Fetal – Fetal Aromatase Deficiency (FAD) with androgens for binding places to androgen receptors 4/ Iatrogenic (Clement 1993, Choi et al. 2000). The etiology of hyperandrogenic states can be Protection of the fetus from the mother’s divided into the four aforementioned groups. The most hyperandrogenism frequent cause is a non-tumor ovarian condition (pregnancy luteoma, hyperreactio luteinalis, PCOS). In The most important factor protecting the fetus contrast, adrenal tumor causes are extremely rare (Dahl et from a mother's hyperandrogenism is the placental al. 2008). A mother’s hyperandrogenism caused by fetal aromatase’s cytochrome P 450 (Illingworth et al. 1992), etiology is created with a deficiency of placental whose mechanism of effect was described above. aromatase. Iatrogenic hyperandrogenism in a pregnant However, this enzyme has a certain limitation. For an woman occurs with the use of preparations containing extreme amount of androgens, e.g. for ovary tumors, the androgens or some progestins (e.g. danazol). functional capacity of aromatase is exceeded and the androgens are not sufficiently removed from the Ovarian tumor causes circulation (Shortle et al. 1987). What’s more, placental aromatase is not capable of aromatising The cause of hyperandrogenism with a mother dihydrotestosterone (DHT), whose level often rises in can be tumors from gonadal mesenchyme, such as hyperandrogenic states, particularly with ovarian granulosa/theca cell tumors, thecoma and tumors from etiology. Increased levels lead to relatively easy Sertoli-Leydig cell (Young et al. 1984). Tumors from virilization of the female fetus (Norwitz 2004). functional tissue are relatively rarely the cause