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  • Huhtaniemi, Riikka; Oksala, Riikka; Knuuttila, Matias; Mehmood, Arfa; Aho, Eija; Laajala, Teemu D.; Nicorici, Daniel; Aittokallio, Tero; Laiho, Asta; Elo, Laura; Ohlsson, Claes; Kallio, Pekka; Mäkelä, Sari; Mustonen, Mika V. J.; Sipila, Petra; Poutanen, Matti (2018)
    The role of adrenal androgens as drivers for castration-resistant prostate cancer (CRPC) growth in humans is generally accepted; however, the value of preclinical mouse models of CRPC is debatable, because mouse adrenals do not produce steroids activating the androgen receptor. In this study, we confirmed the expression of enzymes essential for de novo synthesis of androgens in mouse adrenals, with high intratissue concentration of progesterone (P-4) and moderate levels of androgens, such as androstenedione, testosterone, and dihydrotestosterone, in the adrenal glands of both intact and orchectomized (ORX) mice. ORX alone had no effect on serum P-4 concentration, whereas orchectomized and adrenalectomized (ORX + ADX) resulted in a significant decrease in serum P-4 and in a further reduction in the Low levels of serum androgens (androstenedione, testosterone, and dihydrotestosterone), measured by mass spectrometry. In line with this, the serum prostate-specific antigen and growth of VCaP xenografts in mice after ORX + ADX were markedly reduced compared with ORX alone, and the growth difference was not abolished by a glucocorticoid treatment. Moreover, ORX + ADX altered the androgen-dependent gene expression in the tumors, similar to that recently shown for the enzalutamide treatment. These data indicate that in contrast to the current view, and similar to humans, mouse adrenals synthesize significant amounts of steroids that contribute to the androgen receptor dependent growth of CRPC.
  • Huhtaniemi, Riikka; Sipila, Petra; Junnila, Arttu; Oksala, Riikka; Knuuttila, Matias; Mehmood, Arfa; Aho, Eija; Laajala, Teemu D.; Aittokallio, Tero; Laiho, Asta; Elo, Laura; Ohlsson, Claes; Thulin, Malin Hagberg; Kallio, Pekka; Makela, Sari; Mustonen, Mika V. J.; Poutanen, Matti (2022)
    Antiandrogen treatment resistance is a major clinical concern in castration-resistant prostate cancer (CRPC) treatment. Using xenografts of VCaP cells we showed that growth of antiandrogen resistant CRPC tumors were characterized by a higher intratumor dihydrotestosterone (DHT) concentration than that of treatment responsive tumors. Furthermore, the slow tumor growth after adrenalectomy was associated with a low intratumor DHT concentration. Reactivation of androgen signaling in enzalutamide-resistant tumors was further shown by the expression of several androgen-dependent genes. The data indicate that intratumor DHT concentration and expression of several androgen-dependent genes in CRPC lesions is an indication of enzalutamide treatment resistance and an indication of the need for further androgen blockade. The presence of an androgen synthesis, independent of CYP17A1 activity, has been shown to exist in prostate cancer cells, and thus, novel androgen synthesis inhibitors are needed for the treatment of enzalutamide-resistant CRPC tumors that do not respond to abiraterone.
  • Kohva, Ella; Huopio, Hanna; Hietamäki, Johanna; Hero, Matti; Miettinen, Päivi J.; Raivio, Taneli (2019)
    What is the peripubertal outcome of recombinant human FSH (r-hFSH) treatment during minipuberty in boys with congenital hypogonadotropic hypogonadism (CHH)?Sertoli-cell response to r-hFSH, given during the minipuberty of infancy, appears insufficient to maintain Sertoli cell function throughout childhood, as evaluated by inhibin B measurements.Severe CHH in boys can be diagnosed during the minipuberty of infancy. Combined gonadotropin treatment at that age is suggested to improve testicular endocrine function and future fertility, yet long-term evidence is lacking.In this retrospective cohort study, we describe five CHH boys treated with r-hFSH in Helsinki University Hospital or Kuopio University Hospital between 2004 and 2018. Immediate follow-up data (0.1–1.4 months after cessation of the gonadotropin therapy) was available for four boys and long-term observations (at the age of 10.0–12.8 years) was available for three boys. As a retrospective control cohort, we provide inhibin B values of eight untreated CHH boys at the age of 12.7–17.8 years.Four patients had combined pituitary hormone deficiency, and one had CHARGE syndrome due to a CHD7 mutation. The patients were treated at the age of 0.7–4.2 months with r-hFSH (3.4 IU/kg–7.5 IU/kg per week in 2 or 3 s.c. doses for 3–4.5 months) combined with T (25 mg i.m. monthly for three months for the treatment of micropenis). Inhibin B was chosen as the primary outcome measure.During the r-hFSH + T treatment, inhibin B increased from 76 ± 18 ng/l to 176 ± 80 ng/l (P = 0.04) and penile length increased by 81 ± 50% (P = 0.04). Unexpectedly, two boys with robust inhibin B responses in infancy demonstrated low inhibin B values in peripuberty: declining from 290 ng/l (4 months) to 16 ng/l (12.4 years), and from 207 ng/l (6 months) to 21 ng/l (12.8 years). All boys underwent orchiopexy at 2.0 ± 0.7 years of age. Inhibin B values in long-term follow-up, available for the three boys, did not significantly differ from the untreated CHH controls.Limitations of this retrospective study are the small number and heterogeneity of the patients and their treatment schemes.We describe the first long-term follow-up data on CHH boys treated with r-hFSH and T as infants. The results from this small patient series suggest that the effects of infant r-hFSH treatment may be transient, and further longitudinal studies are required to determine the efficacy of this treatment approach to optimise the fertility potential in this patient population.This work was supported by the Finnish foundation for Pediatric Research, the Academy of Finland and the Emil Aaltonen Foundation. The authors have no competing interests.Non-applicable.