Ovarian damage from chemotherapy and current approaches to its protection

BACKGROUND: Anti-cancer therapy is often a cause of premature ovarian insufficiency and infertility since the ovarian follicle reserve is extremely sensitive to the effects of chemotherapy and radiotherapy. While oocyte, embryo and ovarian cortex cryopreservation can help some women with cancer-induced infertility achieve pregnancy, the development of effective methods to protect ovarian function during chemotherapy would be a significant advantage.OBJECTIVE AND RATIONALE: This paper critically discusses the different damaging effects of the most common chemotherapeutic compounds on the ovary, in particular, the ovarian follicles and the molecular pathways that lead to that damage. The mechanisms through which fertility-protective agents might prevent chemotherapy drug-induced follicle loss are then reviewed.SEARCH METHODS: Articles published in English were searched on PubMed up to March 2019 using the following terms: ovary, fertility preservation, chemotherapy, follicle death, adjuvant therapy, cyclophosphamide, cisplatin, doxorubicin. Inclusion and exclusion criteria were applied to the analysis of the protective agents.OUTCOMES: Recent studies reveal how chemotherapeutic drugs can affect the different cellular components of the ovary, causing rapid depletion of the ovarian follicular reserve. The three most commonly used drugs, cyclophosphamide, cisplatin and doxorubicin, cause premature ovarian insufficiency by inducing death and/or accelerated activation of primordial follicles and increased atresia of growing follicles. They also cause an increase in damage to blood vessels and the stromal compartment and increment inflammation. In the past 20 years, many compounds have been investigated as potential protective agents to counteract these adverse effects. The interactions of recently described fertility-protective agents with these damage pathways are discussed.WIDER IMPLICATIONS: Understanding the mechanisms underlying the action of chemotherapy compounds on the various components of the ovary is essential for the development of efficient and targeted pharmacological therapies that could protect and prolong female fertility. While there are increasing preclinical investigations of potential fertility preserving adjuvants, there remains a lack of approaches that are being developed and tested clinically

Effects of b3-adrenoceptors agonist SR 58611A on gastric acid secretion and histamine release in the dog: comparison with ritodrine.

1. The involvement of beta(3) adrenoceptors in the control of gastric acid secretion and histamine release was investigated in the dog. 2. In conscious dogs, SR 58611A (0.0625-1.0 mg/kg/hr IV) dose dependently inhibited gastric acid secretion induced by pentagastrin. Maximal inhibition (40%) was obtained with the dose of 1 mg/kg. Ritodrine (1 mg/kg/hr IV) also induced a marked inhibition (85%) of gastric acid secretion stimulated by pentagastrin. 3. On 2 deoxy-D-glucose-stimulated acid secretion, both SR 58611A and ritodrine at 1 mg/kg/hr IV showed inhibitory effects. On these experiments, ritodrine, but not SR 58611A, significantly reduced plasma gastrin concentrations. 4. In anaesthetized dogs, histamine concentrations from gastrosplenic vein increased fivefold after the infusion of pentagastrin. SR 58611A(1 mg/kg/hr IV) did not significantly modify the stimulant effect of pentagastrin on histamine release. Tn contrast, ritodrine (1 mg/kg/hr IV) significantly inhibited histamine release induced by pentagastrin. 5. These data suggest that beta(3) adrenoceptors may participate in the negative control of gastric acid secretion in the dog, probably through a histamine-independent mechanism

Comparative bioavailability of two sustained-release theophylline formulations in the dog.

The kinetics of two sustained-release theophylline formulations, Theo-Dur(R) (Recordati, Milano, Italy) and Diffumal(R) (Malesci, Firenze, Italy) were studied in eight beagle dogs. In a first part of the study each animal was injected intravenously with aminophylline dihydrate, Aminomal(R) (Malesci, Firenze, Italy), in order to determine the absolute bioavailability of the two sustained-release theophylline formulations orally administered to the dogs in the second experimental phase, over a period of 9 days, following a balanced two-period cross-over design. Assays for theophylline were performed by high performance liquid chromatography and the pharmacokinetic analysis was performed using the non-compartmental method. The principle of superposition was then applied to predict multiple dose plasma concentrations from experimental single dose data. No significant differences between the two preparations were found with respect to the main pharmacokinetic parameters, showing that the two preparations are bioequivalent. The fact that the differences between experimental and predicted results were not statistically significant allows us to conclude that multiple dose steady state plasma theophylline concentration in the dog can be predicted from experimental single dose data. Furthermore, after repeated treatment, both Diffumal(R) and Theo-Dur(R), given twice daily are able to maintain therapeutic (5-20 mg ml(-1)) plasma theophylline concentrations in the dog