EDITORIAL: EXCESS FETAL ESTROGEN AS AN ETIOLOGICAL CAUSE OF HUMAN CRYPTORCHIDISM

Although it is readily known that the administration of es- tradiol in the rodent can induce cryptorchidism, whether excess estrogens in humans can cause cryptorchidism is highly contro- versial. To understand this debate better one must be conver- sant with the animal data regarding the induction of cryp- torchidism by estradiol. Three different explanations currently exist regarding how increased levels of fetal estrogens could induce cryptorchidism. These different hypotheses center around the ability of estrogen to stabilize the mullerian ducts, the direct antagonistic action of estrogen on gubernacular out- growth and the antiandrogen effect of estrogen. The first hypothesis is based on the ability of estradiol to stabilize the mullerian ducts, thereby preventing mullerian in- hibitory factor involution of the mullerian system. Notably, estrogen does not inhibit mullerian inhibitory factor secretion or action but acts independently to stabilize the mullerian ducts. Stabilization of the mullerian ductal structures results in the intertwining of the gonad with the persistent mullerian structures, thereby anatomically inhibiting descent of the tes- ticle. This hypothesis is probably not functional in the human, since mullerian ductal structures are not usually found in in- fants undergoing surgical exploration for cryptorchidism. The routine absence of mullerian structures in humans with cryp- torchidism would suggest that either excess estrogens do not cause cryptorchidism in humans via this mechanism or alter- natively that excess estrogen secretion in humans occurs in a time specific manner, that is after the dissolution of mullerian structures.1-4 The second hypothesis regarding how excess maternal estro- gens could cause cryptorchidism is based on its direct ability to prevent or reduce gubernacular swelling or outgrowth. This hy- pothesis is based on the findings that the administration of neo- natal estradiol can induce cryptorchidism, while neonatal antian- drogen blockade with flutamide cannot. The ability of neonatal estradiol and the inability of neonatal flutamide to induce cryp- torchidism suggest that estradiol induction of cryptorchidism is not via an antiandrogenic mechanism but rather by a direct estro- genic effect. Investigations into how this induction could occur have revealed that estrogens can directly interfere with the pro- duction of insulin-like growth factor 3, a paracrine growth factor that is manufactured by the Leydig cell and is required for guber- nacular outgrowth. Excess maternal estrogens could therefore in- hibit gubernacular outgrowth and subsequently induce cryp- torchidism via direct estrogenic effect.5-8 The third hypothesis is based on the antiandrogen effects of estrogens. Specifically, estrogen can inhibit testosterone secretion by acting either indirectly to diminish the pituitary secretion of luteinizing hormone or by directly inhibiting testosterone synthesis by the Leydig cell. According to this hypothesis it is the ability of estrogen to decrease serum testosterone that leads to cryptorchidism.5 The concept that excess fetal estradiol is the cause for cryp- torchidism is intellectually appealing. If true, this single finding could be used to explain the etiological cause of cryptorchidism, and its associated risks of infertility and testicular carcino- ma.9-12 In this issue of The Journal Hadz ˘iselimovicet al (page 1694) bolster this concept. They compare and contrast the ex- pression of placental estradiol between newborns with cryp- torchidism and normal male newborns. The authors found an elevated level of estradiol expression in the placenta of neonates with cryptorchidism, which they infer may possibly be corre- lated with an increased level of estradiol in the fetal plasma. Although this assumption may be correct, several missing links need to be filled in to reach this conclusion. In partic- ular, the authors failed to note if the mothers and placentas were matched for the number of pregnancies in their study population. This point is important since higher maternal levels of free estradiol are found in the first compared to later pregnancies.13, 14 Failure to mention whether the control and study populations were matched for parity leaves their cur- rent findings in doubt. The other important missing link is the measurement of the level of free estradiol in the newborn. Indeed, the newborn is figuratively bathed in an ocean of maternal estrogens with a-fetoprotein serving to bind and sequester the untoward effects of free estradiol. Since it is generally accepted that only free estradiol is bioavailable, without the measurement of percent free estradiol in the fetal plasma we are left in a quandary regarding the signif- icance of the current findings of elevated estradiol in the placenta. Although Hadz ˘iselimovicet al help to document that the maternal and placental estradiol are elevated in children with cryptorchidism, it remains to be elucidated if this increased amount is indeed associated with alternations in fetal estradiol and subsequently a cause of cryptorchidism.