TERATOGENICITY AND DRUGS AFFECTING THE FETUS (Part six)

10 - HORMONES

- In the first 9 weeks, the primordial structures are bipotential and become the genital organs.
- From weeks 9-14, the testes secrete androgens and the fetus develops the male phenotype.
- Ovaries do not secrete androgens and the female fetus continues to develop the female phenotype, which concludes around week 20 of pregnancy.
- Exposure to exogenous sex hormones before the 7th week of pregnancy has no effects on external structures.
- Exposure to hormones between weeks 7-12 of pregnancy causes the female genital tissues to respond to androgens and results in complete masculinization.
- Exposure to hormones after week 12 leads to a partial response of fetal tissues up to week 20, resulting in partial masculinization or genital ambiguity.
- The critical period of hormone action on behavior is later than the impact on genital organs and depends on the duration and dose of hormones.
- Hormones (androgens and estrogen) act on specific areas of the brain, being responsible for identity, sexual behavior, aggression levels, and specific behaviors of each sex.

A -Testosterone and anabolic steroids

- Causes increase in body mass and muscle strength.
- Exposure to a female fetus results in various degrees of virilization, causing labioscrotal fusion from exposure in the first trimester and phallic enlargement in later fetal exposure.
- Exposure to androgens in an adult woman causes irreversible virilization, liver disorder, libido disorders.

B - Estrogens

- Studies have shown that oral contraceptives are not associated with congenital anomalies.
- DES (diethylstilbestrol) is grouped as an incomplete carcinogen.
- Malignancy does not depend on the dose of exposure, and the location of the tumor is not influenced by the dose of exposure.
- DES causes structural and functional anomalies.

- Exposure to DES increases the risk for cervical and vaginal intraepithelial neoplasia, it in week 18 causes a disruption of the normal migration of squamous epithelium from the urogenital sinus to the columnar epithelium, leading to broad cervical eversion (ectropion) and ectopic vaginal glandular epithelium (adenosis). These lesions have a high malignant potential.

- The most common anomalies observed in exposure to DES are hypoplastic uterus, T-shaped uterine cavity, cervical septum, damage to the fallopian tubes.

- Uterine malformations are associated with a decrease in endometrial thickness and reduction in uterine perfusion.

- Exposure in males does not affect sexual function and fertility, associated with a high risk for epididymal cysts, cryptorchidism, testicular hypoplasia.

- Males born from mothers exposed to DES during pregnancy are associated with a high risk for hypospadias.

11 - RETINOIDS

- These components, especially vitamin A, are essential for normal cellular growth, tissue differentiation, reproduction, and vision.
- Used for the treatment of skin diseases, breast cancer, respiratory system carcinoma, ovarian cancer, certain leukemias, psoriasis. - Included in category X of drugs.
- We have 2 natural forms of vitamin A:
     a - Beta-carotene, is a precursor of provitamin A. Found in fruits and vegetables and does not cause birth defects.
     b - Retinol is more commonly found in animal liver. High doses of vitamin A are associated with congenital anomalies.

- Common anomalies include: microcephaly, spina bifida, hydrocephaly, facial nerve paralysis, abnormal development of the upper jaw, cleft palate, short limbs, absence or deformation of ears, abnormal development of the cerebellum, malformations of the cerebral cortex, heart defects, thymus anomalies.

- Etretinate is associated with severe anomalies. It is a lipophilic medication, with a plasma half-life of 120 days and can be detected in serum up to 3 years after discontinuation of its use. A woman who has used etretinate should wait 2 years from the discontinuation of the medication and until planning a possible pregnancy.

12 - WARFARIN

- Warfarin is a low molecular weight anticoagulant, which easily crosses the placental barrier and causes anticoagulation for both mother and child.

- Warfarin inhibits the synthesis of vitamin K-dependent coagulation factors (II,VII,IX,X).

- Fetal warfarin syndrome or warfarin embryopathy is caused during the use of warfarin in pregnancy.

- Also known as Di Saia’s syndrome.

- Exposure to warfarin at different periods results in different anomalies, in the first trimester we have anomalies directly related to the teratogenic effect on the development of the central nervous system, in the second and third trimesters related to the damage caused by bleeding and infarction in cerebral structures.

- Exposure in weeks 6-9 of pregnancy causes Warfarin embryopathy, which is associated with nasal hypoplasia and half-face hypoplasia, spontaneous abortion.

- It is dose-dependent and occurs when exceeding a dose of 5 mg per day of warfarin.

- Exposure in the second and third trimesters is associated with a series of deformities in many organs and causes warfarin fetopathy, preterm birth, fetal death in utero.

- Associated with nasal root hypoplasia, laryngomalacia, congenital heart defects, scoliosis, ventriculomegaly, agenesis of the corpus callosum, telebrachydactyly, cerebellar atrophy, microphthalmia, optic atrophy, blindness, uncalcified epiphyses, hypoplasia of fingers, Dandy-Walker malformation, growth delay, mental retardation, deafness, feeding difficulties, contractures, reduced muscle tone, low birth weight, higher risk for bleeding.

13 - RADIATION

- Radiation causes damage to the embryo related to cell death and chromosomal damage.
- So far, there is no evidence that radiation in therapeutic doses causes fetal malformations.
- The most critical and sensitive period to radiation is the first 8-15 weeks of fertilization.
- The most sensitive part of the fetus to radiation is the brain.
- In utero causes microcephaly and mental retardation while later causes leukemia and malignant hematopoietic pathology.